1. 1 Menopause Barbara Sproule, PGY-5 University of Ottawa The Ottawa Hospital

2. 2 Objectives Review the definitions and physiology of perimenopause and menopause in relation to menstrual cycle changes and fertility Review the definitions and physiology of perimenopause and menopause in relation to menstrual cycle changes and fertility Correlate the described physiologic changes with the clinical presentation of menopause, including common signs and symptoms of menopause Correlate the described physiologic changes with the clinical presentation of menopause, including common signs and symptoms of menopause Describe the effects of hormonal changes in the post menopausal woman on lipid metabolism, the cardiovascular system and bone metabolism Describe the effects of hormonal changes in the post menopausal woman on lipid metabolism, the cardiovascular system and bone metabolism

3. Objectives Describe the bio psychosocial impact of menopause Describe the bio psychosocial impact of menopause Describe appropriate investigations in the post menopausal woman Describe appropriate investigations in the post menopausal woman Describe pharmacologic and non pharmacologic approaches to management of menopausal symptoms as well as side effects of treatment on other organ systems Describe pharmacologic and non pharmacologic approaches to management of menopausal symptoms as well as side effects of treatment on other organ systems 3

4. 4 Definitions Menopause : Menopause :  Defined as 12 months of amenorrhea after the final/ last natural menstrual period. It results from the loss of physiological ovarian function. Menopause is equal to one day in a woman’s life. Menopause is equal to one day in a woman’s life. The woman is referred to as being post menopausal once the 12 months of amenorrhea have elapsed. The woman is referred to as being post menopausal once the 12 months of amenorrhea have elapsed. The average age is 51.4 years, however anytime between the ages of 45 and 55 is considered normal. The average age is 51.4 years, however anytime between the ages of 45 and 55 is considered normal.

5. 5 Menopause (Last Natural Period) Symptoms Postmenopause 45 y 50-55 y Premenopause Perimenopause

6. 6 Definitions Early menopause occurs between the ages of 40-45. Early menopause occurs between the ages of 40-45. Loss of ovarian function occuring before the age of 40 is referred to as premature ovarian failure/insufficiency. This results in early loss of the protective effects of estrogen and may increase risk for osteoporosis and heart disease later in life. Loss of ovarian function occuring before the age of 40 is referred to as premature ovarian failure/insufficiency. This results in early loss of the protective effects of estrogen and may increase risk for osteoporosis and heart disease later in life. Late menopause occurs after the age of 55 and results in a longer exposure to estrogen. Late menopause occurs after the age of 55 and results in a longer exposure to estrogen.

7. 7 Definitions Perimenopause :  A transition period leading to menopause beginning with altered ovarian hormone production.  Lasts 2-8 years with an average duration of 5 years before the last menstrual period, and continues until 1 year after the last natural menstrual period. May start as early as the mid 30s. May start as early as the mid 30s.

8. 8 Definitions Perimenopause Associated with fluctuating hormone levels varying within the same cycle (low-normal- high) Associated with fluctuating hormone levels varying within the same cycle (low-normal- high) Varied symptoms of menopause as well as symptoms of estrogen excess, such as breast tenderness, all within the same cycle. Varied symptoms of menopause as well as symptoms of estrogen excess, such as breast tenderness, all within the same cycle. Characterized by irregularity of menstrual cycles and anovulation. Characterized by irregularity of menstrual cycles and anovulation.

9. 9 Menstrual Periods in the Perimenopause 35 40 45 50 Regular cycles Shortened cycles Irregular cycles Periods cease Estrogen deficiency symptoms

10. 10 Age at Menopause 0 50 100 404551.45560 Pre- mature Late Early Average Percentage of women Age (years) *

11. 11 Demographics In 2003 there were 4,000,000 In 2003 there were 4,000,000 postmenopausal Canadian women. postmenopausal Canadian women. One woman will enter the menopause One woman will enter the menopause every 10 seconds until 2015. every 10 seconds until 2015.

12. 12 Menopause: Symptoms Hot flashes Hot flashes Night sweats Night sweats Sleep disturbance Sleep disturbance Poor memory Poor memory Poor concentration Poor concentration Irritability/emotional lability Irritability/emotional lability Depression Depression Bélisle S, et al. J Obstet Gynaecol Can 2006; 28(Suppl 1):S7-S94.

13. 13 Menopause: Symptoms Fatigue Fatigue Myalgias and athralgias Myalgias and athralgias Urinary frequency and urgency Urinary frequency and urgency Vaginal dryness Vaginal dryness Diminished sexual drive and response Diminished sexual drive and response

14. 14 Menopause symptoms Vasomotor symptoms affect 60% to 80% of women entering menopause. Vasomotor symptoms affect 60% to 80% of women entering menopause. 60% of postmenopausal women experience hot flashes for less than 7 years. Up to 15% report that hot flashes persist for 15 years or more. 60% of postmenopausal women experience hot flashes for less than 7 years. Up to 15% report that hot flashes persist for 15 years or more. Normally, the body maintains an optimal temperature via the thermoneutral zone. Normally, the body maintains an optimal temperature via the thermoneutral zone. Metabolic activity is regulated through vasodilatation and sweating when overheated and shivering when cold. Metabolic activity is regulated through vasodilatation and sweating when overheated and shivering when cold.

15. 15 Menopause symptoms Postmenopausal women are thought to have narrowing of this “thermoneutral zone”. Small changes in temperature can evoke the regulatory response of sweating or shivering. Postmenopausal women are thought to have narrowing of this “thermoneutral zone”. Small changes in temperature can evoke the regulatory response of sweating or shivering. Risk factors for hot flashes : obesity, cigarette smoking, triggers (alcohol, warm ambient environment, hot drinks). Risk factors for hot flashes : obesity, cigarette smoking, triggers (alcohol, warm ambient environment, hot drinks). These form the basis for lifestyle recommendations to reduce vasomotor symptoms. These form the basis for lifestyle recommendations to reduce vasomotor symptoms. Freeman EW, Sherif K. Prevalence of hot flushes and night sweats around the world: a systematic review. Climacteric 2007;10:197–214. Schwingl PJ, Hulka BS, Harlow SD. Risk factors for menopausal hot flashes. Obstet Gynecol 1994;84:29–34.

16. 16 Symptomatic Freedman RR. Am J Med 2005;118:124S-130S. Upper threshold (Upper set point) Lower threshold (Lower set point) Sweating Shivering Thermo- neutral Zone (homeostatic range) Normal Body temperature Sweating Shivering Core Body Temp Menopause symptoms

17. 17 0 5 10 15 20 25 30 35 40 45 50 Number of Years Women Reported Having Hot Flashes Number of Subjects Some Women Experience Hot Flashes for a Few Months or Up to Many Years Data from a survey of 438 untreated women, aged 29 to 82 years, who experienced hot flashes regardless of menopausal status. 0 2 46810121416 18 20222428303641 Adapted from Kronenberg F. Ann N Y Acad Sci 1990;592:52-86. Mean age of natural menopause was 49.5 years; mean age of surgical menopause was 43.7 years.

18. 18 Menopause: Health Risks Low estrogen confers increased risks of : Cardiovascular disease Cardiovascular disease Osteoporosis Osteoporosis Colorectal cancer Colorectal cancer Quality of life issues (vasomotor symptoms, sexual concerns, depression, cognitive decline) Quality of life issues (vasomotor symptoms, sexual concerns, depression, cognitive decline)

19. 19 Lifestyle Counselling : Perceptions of Canadian Women 0 10 20 30 40 50 41% 27% 16% 8% 2% 6% Causes of Death Breast Cancer Cancer (non-specific) Heart / BP / Stroke Lung Cancer Uterine Cancer Other/Don’t Know Percentage

20. Cardiovascular Disease Facts  Menopause compounds the traditional CVD risk factors:  Central adiposity  Glucose intolerance  Dyslipidemia  Endothelial dysfunction  20

21. 21 Cardiovascular Disease Facts #1 cause of death #1 cause of death Onset 10-15 years after menopause (Later in life) Onset 10-15 years after menopause (Later in life) By age 75 : 1/3 of women are affected by CVD By age 75 : 1/3 of women are affected by CVD 1/6 of women die from CVD 1/6 of women die from CVD Menopause has no direct effect on plasma glucose and insulin Menopause has no direct effect on plasma glucose and insulin Main effects of estrogen defficiency is on lipid profile Cholesterol changes Cholesterol changes  HDL-C  HDL-C  LDL-C  LDL-C Vascular effects as a result of dyslipidemia Vascular effects as a result of dyslipidemia -  plaque development -  plaque development -  ability to dilate

22. LIPID CHANGES In the late perimenopause and the early menopause (within a year), the following changes occur.  LDL increases (6-10 %)  Triglycerides increase (3-11%)  Apolipoprotein B increases  Total cholesterol increases (mainly from LDL increase)  HDL –variable 6 studies 6 % 3 studies 8-15% 3 studies 8-15% 6 studies unchanged 6 studies unchanged 22

23. LIPID CHANGES  HDL depends on environmental factors  Lack of exercise (decreases HDL)  Alcohol consumption ( increases HDL)  Increased BMI ( decreases HDL)  No genetic factors  Increased Total cholesterol /HDL ratio resulting in faster arterial aging 23

24. Normal bone Osteoporosis compromised bone strength bone density and bone quality. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. Definition of Osteoporosis NIH Consensus Development Panel on Osteoporosis. JAMA 2001

25. Age and Fracture Risk

26. The hip, spine and wrist are the most common sites of fracture in osteoporosis. A 50 year old woman has a 40% chance of any fracture over her lifetime.

28. Major Risk Factors (1 or more) Major Risk Factors (1 or more) Age >65 years Age >65 years Hypogonadism (no estrogen- menopause) Hypogonadism (no estrogen- menopause) Family Hx of osteoporosis Family Hx of osteoporosis Vertebral fracture Vertebral fracture Fragility fracture under age 40 Fragility fracture under age 40 Propensity to fall Propensity to fall Early menopause (<45) Early menopause (<45) Other (glucocorticoid-steroid therapy >3 months, malabsorption etc.) Other (glucocorticoid-steroid therapy >3 months, malabsorption etc.)

29. Minor Risk Factors (2 or more) Minor Risk Factors (2 or more) Smoker Smoker Weight less than 57 kgs (125 lbs) Weight less than 57 kgs (125 lbs) Excessive intake of caffeine or alcohol Excessive intake of caffeine or alcohol Past clinical hyperthyroidism Past clinical hyperthyroidism Anticonvulsant therapy Anticonvulsant therapy Low calcium intake Low calcium intake Rheumatoid arthritis Rheumatoid arthritis Chronic heparin therapy Chronic heparin therapy

30. Prevention of Osteoporosis

31. CalciumCalcium Essential mineral for good bone health Essential mineral for good bone health Recommended intakes (combination of diet and supplements): Recommended intakes (combination of diet and supplements): Peri-menopause - 1000 mg/d Peri-menopause - 1000 mg/d Post-menopause - 1200 mg/d Post-menopause - 1200 mg/d Can be taken in divided doses Can be taken in divided doses Food sources: dairy, canned fish, nuts, fortified foods, some leafy greens Food sources: dairy, canned fish, nuts, fortified foods, some leafy greens Calcium therapy alone is insufficient Calcium therapy alone is insufficient in patients at high risk for fracture in patients at high risk for fracture

32. Vitamin D Important for maintenance of bone health Important for maintenance of bone health Most recommend intake of 1,000 IU/d of Vitamin D3 Most recommend intake of 1,000 IU/d of Vitamin D3 Deficiency common due to limited sun exposure / use of sunscreen Deficiency common due to limited sun exposure / use of sunscreen Food sources: fortified milk, soy beverages, and margarine, fish, liver, egg yolk Food sources: fortified milk, soy beverages, and margarine, fish, liver, egg yolk Sun exposure 20 min / day Sun exposure 20 min / day

33. Physical Activity

34. Modified from Drinkwater BL. 2 nd World Congress on Aging Male, Geneva, 2000. Exercise and balance training Improved coordination Better balance Greater strength Less chances of falling Less fractures Less damage from fall Exercise and Balance Training: Effect on Falls and Fractures

35. 35 Case Study Mrs. M is a 54-year-old woman Mrs. M is a 54-year-old woman Her last menstrual period was 18 months ago. Her last menstrual period was 18 months ago. She presents to your office complaining of unbearable hot flashes. She presents to your office complaining of unbearable hot flashes.

36. 36 History Establish that this is a symptom of menopause and ask about presence of other symptoms of menopause. Establish that this is a symptom of menopause and ask about presence of other symptoms of menopause. Assess the severity of symptoms and the impact on her function and quality of life. Assess the severity of symptoms and the impact on her function and quality of life. Obtain information regarding past and current therapies used to alleviate symptoms and effectiveness (i.e herbals, etc). Obtain information regarding past and current therapies used to alleviate symptoms and effectiveness (i.e herbals, etc). Obtain personal and family histories to investigate for risk factors (CVD, osteoporosis, cancers). Obtain personal and family histories to investigate for risk factors (CVD, osteoporosis, cancers). Establish any contraindications to HT. Establish any contraindications to HT.

37. 37 Contraindications to Hormonal therapy Hormone- dependent cancers (breast cancer, endometrial cancer) Hormone- dependent cancers (breast cancer, endometrial cancer) Active or recent arterial thromboembolic disease (MI, Angina) Active or recent arterial thromboembolic disease (MI, Angina) Venous thromboembolism, PE Venous thromboembolism, PE Severe active liver disease Severe active liver disease Uninvestigated abnormal uterine bleeding Uninvestigated abnormal uterine bleeding

38. 38 Physical Exam General : Blood pressure, Weight, BMI General : Blood pressure, Weight, BMI Cardiac / respiratory exam Cardiac / respiratory exam Breast Exam Breast Exam Abdominal exam Abdominal exam PAP test and pelvic exam : looking for pelvic masses, signs of vulvo-vaginal atrophy, decreased vaginal calibre. PAP test and pelvic exam : looking for pelvic masses, signs of vulvo-vaginal atrophy, decreased vaginal calibre.

39. 39 Investigations Hormonal profile : FSH, LH, E2 Hormonal profile : FSH, LH, E2 Fasting lipids/glucose Fasting lipids/glucose Pelvic ultrasound (if indicated) Pelvic ultrasound (if indicated) Mammogram Mammogram Bone mineral density (BMD) Bone mineral density (BMD)

40. 40 Counselling - Preventive Care for Menopausal Women  Monitor BP, glucose, lipid profile, thyroid function  Regular Pap smear  Regular breast exam (provincial screening program- OBSP)  Mammogram  Colorectal cancer screening  Selective bone density testing  Flu shot  Safe sex  Fall-proofing recommendations for seniors

41. 41 First Line Health Promotion/ Disease Prevention Measures ExerciseCalcium Vitamin D Smoking Cessation Moderation of Alcohol Intake

42. 42 Treatment of vasomotor symptoms Systemic Hormonal therapy  Proven efficacy to treat menopausal symptoms.  Not meant to replace endogenous hormone.  Approved for the symptomatic relief of hot flashes affecting quality of life.  Other benefits include improvement of vaginal dryness and prevention of osteoporosis.

43. 43 SOGC Guidelines : VMS 1. Lifestyle modifications, including reducing core body temperature, regular exercise, weight management, smoking cessation, and avoidance of known triggers such as hot drinks and alcohol may be recommended to reduce mild vasomotor symptoms. (IC) 2. Health care providers should offer HT (estrogen alone or EPT) as the most effective therapy for the medical management of menopausal symptoms. (IA)

44. 44 SOGC Guidelines : VMS 3. Progestins alone or low-dose oral contraceptives can be offered as alternatives for the relief of menopausal symptoms during the menopausal transition. (IA) 4. Nonhormonal prescription therapies, including treatment with certain antidepressant agents (venlafaxine), gabapentin, clonidine, and bellergal, may afford some relief from hot flashes but have their own side effects. These alternatives can be considered when HT is contraindicated or not desired. (IB) These alternatives can be considered when HT is contraindicated or not desired. (IB)

45. 45 SOGC Guidelines : VMS  There is limited evidence of benefit of most complementary and alternative approaches for the management of hot flashes. Without good evidence for effectiveness, and in the face of minimal data on safety, these approaches should be advised with caution.(IB) Women should be advised that, until January 2004, most natural health products were introduced into Canada as “food products” and did not fall under the regulatory requirements for pharmaceutical products. As such, most have not been rigorously tested for the treatment of moderate to severe hot flashes, and many lack evidence of efficacy and safety. (IB) Women should be advised that, until January 2004, most natural health products were introduced into Canada as “food products” and did not fall under the regulatory requirements for pharmaceutical products. As such, most have not been rigorously tested for the treatment of moderate to severe hot flashes, and many lack evidence of efficacy and safety. (IB) SOGC. J Obstet Gynaecol Can 2009; 31(Suppl 1):S1-S46.

46. 46 SOGC recommendations : VMS Several recent systematic reviews have examined complimentary options for treatment of moderate to severe vasomotor symptoms. Several recent systematic reviews have examined complimentary options for treatment of moderate to severe vasomotor symptoms. None of these found any single complementary therapy to have proven efficacy for moderate to severe hot flashes. None of these found any single complementary therapy to have proven efficacy for moderate to severe hot flashes. A direct head-to-head comparison of HT versus black cohosh, soy, or multibotanicals showed only HT to have an effect greater than that of placebo. A direct head-to-head comparison of HT versus black cohosh, soy, or multibotanicals showed only HT to have an effect greater than that of placebo. 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.

47. 47 HT and Cardiovascular disease risks Mrs. M is concerned about cardiac risks associated with HRT Mrs. M is concerned about cardiac risks associated with HRT “I heard a big study showed more heart attacks in people taking hormones” “I heard a big study showed more heart attacks in people taking hormones” How do you address this concern? How do you address this concern?

48. 48 Women’s Health Initiative (WHI) Asymptomatic patients, average age 63 years, 1/3 > 70 years, with high incidence of diabetes and untreated hypertension. Asymptomatic patients, average age 63 years, 1/3 > 70 years, with high incidence of diabetes and untreated hypertension. Study used conjugated estrogens (0.625 mg CES and 2.5 mg of medroxyprogesterone acetate = provera). Study used conjugated estrogens (0.625 mg CES and 2.5 mg of medroxyprogesterone acetate = provera). Reanalysis actually showed that only a small subgroup of smokers had increased risk of cardiac events. Reanalysis actually showed that only a small subgroup of smokers had increased risk of cardiac events. The conclusion should have been: don’t use these medications in elderly asymptomatic women. The conclusion should have been: don’t use these medications in elderly asymptomatic women. This set back female healthcare by a decade. This set back female healthcare by a decade. Rossouw JE, et al. JAMA 2002; 288(3):321-33.

49. 49 Consequences of the Initial WHI Reports Many doctors and patients became fearful of HT. Many doctors and patients became fearful of HT. Many doctors advised discontinuation of HRT and 50% of users stopped. Many doctors advised discontinuation of HRT and 50% of users stopped. This fueled the multibillion-dollar market in alternate and complementary products. This fueled the multibillion-dollar market in alternate and complementary products. As many as 25% of those who stopped HT returned to their doctors for “permission” to resume treatments. As many as 25% of those who stopped HT returned to their doctors for “permission” to resume treatments. A new generation of women have become hormone savvy and want to participate in their menopause therapy choices. A new generation of women have become hormone savvy and want to participate in their menopause therapy choices.

50. 50 Current Evidence: HT and CVD Paradox HT within five years of removal of the ovaries or in premature ovarian failure is cardioprotective. HT within five years of removal of the ovaries or in premature ovarian failure is cardioprotective. HT should be offered to women with premature ovarian failure or early menopause (IA), and it can be recommended until the age of natural menopause (IIIC)- 2006. HT should be offered to women with premature ovarian failure or early menopause (IA), and it can be recommended until the age of natural menopause (IIIC)- 2006. Estrogen therapy can be offered to women who have undergone surgical menopause for the treatment of endometriosis. (IA)-2006 Estrogen therapy can be offered to women who have undergone surgical menopause for the treatment of endometriosis. (IA)-2006

51. 51 Current Evidence : HT and CVD Paradox There is no convincing evidence for an increase in the risk of cardiovascular disease in newly menopausal women starting hormone therapy; women should be reassured about this ---- (New in SOGC 2009). There is no convincing evidence for an increase in the risk of cardiovascular disease in newly menopausal women starting hormone therapy; women should be reassured about this ---- (New in SOGC 2009). Is HT cardioprotective in newly menopausal women? Is HT cardioprotective in newly menopausal women? We will probably never get the answer: to demonstrate a 10% reduction in cardiovascular mortality in women aged 55 to 59 years, 186,000 women have to remain compliant with hormones or placebo for 10 years. We will probably never get the answer: to demonstrate a 10% reduction in cardiovascular mortality in women aged 55 to 59 years, 186,000 women have to remain compliant with hormones or placebo for 10 years.

52. 52 Critical window hypothesis Suggest that the use of HT at the onset of menopause could be cardioprotective whereas later initiation could cause adverse coronary events as seen in the WHI Suggest that the use of HT at the onset of menopause could be cardioprotective whereas later initiation could cause adverse coronary events as seen in the WHI This theory suggests that the prothrombotic or plaque-destabilizing effects of HT in women with established CAD may account for an initial increase in the incidence of coronary artery events in older women, but that the healthy coronary arteries of younger women benefit from the anti-atherogenic effects of estrogen. This theory suggests that the prothrombotic or plaque-destabilizing effects of HT in women with established CAD may account for an initial increase in the incidence of coronary artery events in older women, but that the healthy coronary arteries of younger women benefit from the anti-atherogenic effects of estrogen. Lobo RA. Evaluation of cardiovascular event rates with hormonal therapy in healthy, early menopausal women: results from two large clinical trials. Arch Intern Med 2004;164:482–4. Lobo RA. Evaluation of cardiovascular event rates with hormonal therapy in healthy, early menopausal women: results from two large clinical trials. Arch Intern Med 2004;164:482–4.

53. 53 HT and VTE risks Mrs. M is concerned about VTE risk associated with HRT Mrs. M is concerned about VTE risk associated with HRT “I read something about a risk of blood clots when taking hormones” How do you address this concern? How do you address this concern?

54. 54 HT and VTE Risks HRT very slightly increases the risk of a blood clot (2-3 additional cases per 10,000 users). HRT very slightly increases the risk of a blood clot (2-3 additional cases per 10,000 users). The risk is greatest in the first year of use. The risk is greatest in the first year of use. In the WHI the HR was 4.0 in year 1 and fell to 1.04 by year 6. In the WHI the HR was 4.0 in year 1 and fell to 1.04 by year 6.

55. 55 HT and VTE Risks Age is a much greater risk factor: compared to a baseline at 50-59 years, risk doubles at 60-69 years and quadruples at 70-79 years. Age is a much greater risk factor: compared to a baseline at 50-59 years, risk doubles at 60-69 years and quadruples at 70-79 years. Risk reduced with lower doses and transdermal estrogen. Risk reduced with lower doses and transdermal estrogen. Cushman M, Kuller LH, Prentice R, et al. JAMA 2004;292:1573-80. Curb JD, Prentice RL, Bray PF, et al. Arch Intern Med 2006; 166:772-80. Silverstein MD, Heit JA, Mohr DN, et al. Arch Intern Med 1998; 158:585-93. Canonico M, Oger E, Plu-Bureau G, et al. Circulation 2007; 115(7):840-5.

56. 56 HT and Stroke To reduce the risk of stroke in women taking HT, risk factors should be addressed. To reduce the risk of stroke in women taking HT, risk factors should be addressed. Use the lowest effective dose, but no absolute time limit. Use the lowest effective dose, but no absolute time limit.

57. 57 HT and breast cancer Mrs. M is concerned about breast-cancer risk associated with HT. Mrs. M is concerned about breast-cancer risk associated with HT. “I read something about the risk of breast cancer in women taking hormones” How do you address this concern? How do you address this concern?

58. 58 HT and Breast Cancer Health care providers should periodically review the risks and benefits of prescribing HT to a menopausal woman in light of the association between duration of use and breast cancer risk. (IA) Health care providers should periodically review the risks and benefits of prescribing HT to a menopausal woman in light of the association between duration of use and breast cancer risk. (IA) Health care providers may prescribe HT for menopausal symptoms in women at increased risk of breast cancer with appropriate counselling and surveillance. (IA) Health care providers may prescribe HT for menopausal symptoms in women at increased risk of breast cancer with appropriate counselling and surveillance. (IA) Health care providers should clearly discuss the uncertainty of risks associated with HT after a diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB) Health care providers should clearly discuss the uncertainty of risks associated with HT after a diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB)

59. 59 HT and Breast Cancer Risks Lifetime exposure to hormones is linked to hormone- receptor-positive breast cancer; this risk is 4.6% for the ages 50-70 years. Lifetime exposure to hormones is linked to hormone- receptor-positive breast cancer; this risk is 4.6% for the ages 50-70 years. Family history is a separate risk. Family history is a separate risk. Factors such as lack of exercise, gaining weight and alcohol consumption raise the risk; 1/3 of postmenopausal breast cancers could be avoided by lifestyle modification. Factors such as lack of exercise, gaining weight and alcohol consumption raise the risk; 1/3 of postmenopausal breast cancers could be avoided by lifestyle modification. Sprague BL, Trentham-Dietz A, Egan KM, et al. Am J Epidemiol 2008; 168(4):404-11. Sprague BL, Trentham-Dietz A, Egan KM, et al. Am J Epidemiol 2008; 168(4):404-11. Sprague BL, et al. Am J Epidemiol 2008; 168(4):404-11.

60. 60 HT and Breast Cancer Risks Many studies indicate a small increased risk of breast cancer, with longer-term use of hormone therapy Many studies indicate a small increased risk of breast cancer, with longer-term use of hormone therapy WHI study: CEE (0.625 mg) and MPA (2.5 mg) WHI study: CEE (0.625 mg) and MPA (2.5 mg) 26% increased risk of breast cancer with treatment vs. placebo (8 additional cases per 10,000 person-years: absolute excess risk) 26% increased risk of breast cancer with treatment vs. placebo (8 additional cases per 10,000 person-years: absolute excess risk) no increased risk with unopposed estrogen* no increased risk with unopposed estrogen* Rossouw JE, Anderson GL, Prentice RL, et al.JAMA 2002; 288:321-33. Rossouw JE, Anderson GL, Prentice RL, et al.JAMA 2002; 288:321-33. Anderson GL, Limacher M, Assaf AR, et al. JAMA 2004; 291(14):1701-12. Anderson GL, Limacher M, Assaf AR, et al. JAMA 2004; 291(14):1701-12. 2..

61. 61 HT and Breast Cancer Risks WHI study finding of a 26% increased risk “is meaningless without information on the background risk of breast cancer by age group.” WHI study finding of a 26% increased risk “is meaningless without information on the background risk of breast cancer by age group.” Risk translated into an absolute increased risk of 8 additional cases per 10,000 HT users per year in the older population of the WHI. Risk translated into an absolute increased risk of 8 additional cases per 10,000 HT users per year in the older population of the WHI.

62. 62 HT and Breast Cancer Risks SOGC 2009 Health care providers should periodically review the risks and benefits of prescribing HT to a menopausal woman in light of the association between duration of use and breast cancer risk. (IA) Health care providers should periodically review the risks and benefits of prescribing HT to a menopausal woman in light of the association between duration of use and breast cancer risk. (IA) Health care providers may prescribe HT for menopausal symptoms in women at increased risk of breast cancer with appropriate counselling and surveillance. (IA) Health care providers may prescribe HT for menopausal symptoms in women at increased risk of breast cancer with appropriate counselling and surveillance. (IA) Health care providers should clearly discuss the uncertainty of risks associated with HT after a diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB) Health care providers should clearly discuss the uncertainty of risks associated with HT after a diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB)

63. 63 Other Risk Factors for Breast Cancer with Hazard Ratios of Approximately 1.3 Early menarche Early menarche Late menopause Late menopause Postmenopausal obesity Postmenopausal obesity First pregnancy after age 30 years First pregnancy after age 30 years Not breastfeeding Not breastfeeding No regular exercise No regular exercise Excess alcohol Excess alcohol SOGC. J Obstet Gynaecol Can 2009; 31(Suppl 1):S1-S46.

64. 64 HT and Breast Cancer Risks Breast density Increased breast density has been found to be an independent risk factor for breast cancer. Increased breast density has been found to be an independent risk factor for breast cancer. Studies have indicated a 15% to 20% decrease in mammographic sensitivity in hormone users who have dense breasts. Studies have indicated a 15% to 20% decrease in mammographic sensitivity in hormone users who have dense breasts. Women receiving postmenopausal HT in the WHI were found to have increased breast density and a greater frequency of abnormal mammograms compared with those receiving placebo. Women receiving postmenopausal HT in the WHI were found to have increased breast density and a greater frequency of abnormal mammograms compared with those receiving placebo. Even though breast density can be increased by the use of estrogen with a progestin, it has never been shown that an acquired increase in density, as in hormone treatment, increases breast cancer risk. Even though breast density can be increased by the use of estrogen with a progestin, it has never been shown that an acquired increase in density, as in hormone treatment, increases breast cancer risk.

65. 65 Urogenital atrophy: Time Does Not Heal Vaginal dryness  Often a first sign of menopause  Progressive with time  Experienced by > 50% of women  Discomfort  Dyspareunia (pain with intercourse)  Bleeding  Post-coital bleeding / discharge  Urinary urgency / frequency  Urinary incontinence

66. 66 Approximately 4 million postmenopausal Canadian women 1 Approximately 4 million postmenopausal Canadian women 1 1.6 million (40%) have urogenital atrophy 2 1.6 million (40%) have urogenital atrophy 2 Only 1 in 5 will talk to their doctor about it 3 Only 1 in 5 will talk to their doctor about it 3 1.SOGC Consensus Conference on Menopause and Osteoporosis, 2002 Update. 2.Johnston S, et al. SOGC Conference Highlights. June 2003. 3.Pandit L, et al. Am J Med Sci 1997;314(4):228-31. Urogenital Atrophy: An unspoken concern Unlike VMS, urogenital atrophy will progressively worsen with time

67. 67 Urogenital Atrophy Local Vaginal estrogen  Treatment of choice for vaginal atrophy in the absence of bothersome vasomotor symptoms. Available as :  Cream - premarin vaginal cream, estragyn cream. (2-3x a week)  Vaginal suppository – Vagifem (2-3x a week)  Vaginal ring – estring (q 3 months)

68. 68 Bioidentical HT Mrs. M is curious about the issue of bio-identical hormones Mrs. M is curious about the issue of bio-identical hormones “I saw a television show during which some beauty icons said bio-identical hormones are much better and safer” “I saw a television show during which some beauty icons said bio-identical hormones are much better and safer” How do you address this? How do you address this?

69. 69 Bio-identical hormones To scientists and health care providers, bio-identical means chemically identical to the hormones produced by women (mainly the ovaries)--- estrone, 17B- estradiol, estriol, progesterone and testosterone. To scientists and health care providers, bio-identical means chemically identical to the hormones produced by women (mainly the ovaries)--- estrone, 17B- estradiol, estriol, progesterone and testosterone. Bio-identical hormonal therapy means medication that provides one or more of these hormones as the active ingredient. Bio-identical hormonal therapy means medication that provides one or more of these hormones as the active ingredient. Bioidentical hormones are available as Bioidentical hormones are available as (i) Government approved, well tested, commercial, brand name prescription drugs. (i) Government approved, well tested, commercial, brand name prescription drugs. (ii) Custom-compounded formulations. (ii) Custom-compounded formulations.

70. 70 Bio-identical hormones Prescription bio-identicals include Prescription bio-identicals include (i) 17B-estradiol preparations- oral estrace, estrace vaginal cream (U.S.A), all transdermal preparations, estring. (i) 17B-estradiol preparations- oral estrace, estrace vaginal cream (U.S.A), all transdermal preparations, estring. (ii) Progesterone capsules—micronized progesterone (prometrium).

71. 71 Bio-identical hormones Custom- compounded formulations Not tested for safety and efficacy yet being offered as safer and more effective alternatives to government approved medications. Not tested for safety and efficacy yet being offered as safer and more effective alternatives to government approved medications. Batch to batch variation ?? sterility. Batch to batch variation ?? sterility. Expensive and not reimbursed by third party payers. Expensive and not reimbursed by third party payers.

72. 72 Bio-identical hormones Custom compounded preparations often include estriol (10% activity of E2). Custom compounded preparations often include estriol (10% activity of E2). Tri-estrogen mixture: 80% estriol, 10% estrone, 10% estradiol (promoted as not increasing the risk of breast cancer---BUT estriol can still have stimulatory effects on the breast and endometium). Tri-estrogen mixture: 80% estriol, 10% estrone, 10% estradiol (promoted as not increasing the risk of breast cancer---BUT estriol can still have stimulatory effects on the breast and endometium). Topical progesterone preparations have not been shown to counter the stimulatory effects of estrogen on the uterus. Topical progesterone preparations have not been shown to counter the stimulatory effects of estrogen on the uterus.

73. 73 Bio-identical hormones Natural is not synonymous with bio-identical. Often used to refer to hormonal preparations of plant origin which may have undergone multiple chemical reactions during synthesis. Natural is not synonymous with bio-identical. Often used to refer to hormonal preparations of plant origin which may have undergone multiple chemical reactions during synthesis. Salivary hormone testing is not proven to be reliable and accurate and there is no such thing as the “right amount of hormones”. A woman’s physical comfort may not be related to her absolute hormonal status. Salivary hormone testing is not proven to be reliable and accurate and there is no such thing as the “right amount of hormones”. A woman’s physical comfort may not be related to her absolute hormonal status. The North American Menopause Society ( NAMS) does not recommend custom- compounded preparations over well tested government approved products. The North American Menopause Society ( NAMS) does not recommend custom- compounded preparations over well tested government approved products.

74. 74 Routes of estrogen delivery Mrs. M wants to know more about the different formulations of HRT Mrs. M wants to know more about the different formulations of HRT “On that same television show, they said that creams are better than pills. Is that true?” “On that same television show, they said that creams are better than pills. Is that true?” How do you address this? How do you address this?

75. 75 The Routes of Estrogen Delivery Oral estrogen has drawbacks: Oral estrogen has drawbacks: raises fibrinogen and other coagulation factors raises fibrinogen and other coagulation factors raises C-reactive protein raises C-reactive protein raises triglycerides by 25% raises triglycerides by 25% raises sex-hormone-binding globulin raises sex-hormone-binding globulin Transdermal estrogen does not have these negative effects Transdermal estrogen does not have these negative effects Transdermal estrogen is available as a gel or patch Transdermal estrogen is available as a gel or patch Hirvonen E, Cacciatore B, Wahlström T, et al. Br J Obstet Gynaecol 1997; 104 (Suppl 16):26-31. Hirvonen E, et al. Br J Obstet Gynaecol 1997; 104(Suppl 16):26-31.

76. 76 The Routes of Estrogen Delivery Advantages of the Transdermal approach Advantages of the Transdermal approach Provides 17B estradiol structurally similar to ovarian source (oral preparations also available). Provides 17B estradiol structurally similar to ovarian source (oral preparations also available). Avoids first pass effect on the liver. Avoids first pass effect on the liver. Relatively stable plasma levels. Relatively stable plasma levels. Permits measurement of serum estradiol in cases of necessary dose adjustments. Permits measurement of serum estradiol in cases of necessary dose adjustments.

77. 77 Choice of specific HT 17-beta estradiol is the principal naturally occurring estrogen in females 17-beta estradiol is the principal naturally occurring estrogen in females reductions in this hormone lead to the symptoms of menopause, as well as to an increase in long-term health risks such as heart disease, osteoporosis and bowel cancer. reductions in this hormone lead to the symptoms of menopause, as well as to an increase in long-term health risks such as heart disease, osteoporosis and bowel cancer. logically hormone therapy should be aimed at the restoration of the bio- identical hormone. logically hormone therapy should be aimed at the restoration of the bio- identical hormone.

78. 78 Choice of specific HT Mrs. M requests counseling regarding what specific type of estrogen or progesterone she should use. Mrs. M requests counseling regarding what specific type of estrogen or progesterone she should use. How do you address this? How do you address this?

79. 79 Choice of specific HT Conjugated equine estrogen (CEE/premarin) is composed of more than 10 estrogens largest component being estrone (45%). Conjugated equine estrogen (CEE/premarin) is composed of more than 10 estrogens largest component being estrone (45%). Pharmacologic effect is the sum of activity of all the component estrogens. Pharmacologic effect is the sum of activity of all the component estrogens. The majority of component estrogens have never been identified. The majority of component estrogens have never been identified.

80. 80 Choice of specific HT Progestins are not Progesterone. Progestins are not Progesterone. Progesterone is the naturally occurring progestational agent in females; it is bio- identical. Progesterone is the naturally occurring progestational agent in females; it is bio- identical. Progestins are synthetic drugs used to mimic some of the effects of progesterone. Progestins are synthetic drugs used to mimic some of the effects of progesterone.

81. 81 HT summary Estrogen: Use the lowest dose of estrogen that alleviates symptoms; this could be conjugated estrogen pill 0.3 mg, estradiol 0.5 mg, a 25 ug patch or estradiol gel 1 metered dose. Use the lowest dose of estrogen that alleviates symptoms; this could be conjugated estrogen pill 0.3 mg, estradiol 0.5 mg, a 25 ug patch or estradiol gel 1 metered dose. Titrate the dose to the individual patient; symptom relief is often a better indicator than blood levels. Titrate the dose to the individual patient; symptom relief is often a better indicator than blood levels. Commercially available gels and patches have better quality control than compounded gels and creams made by pharmacists. Commercially available gels and patches have better quality control than compounded gels and creams made by pharmacists.

82. 82 HT Summary Progesterone: Micronized progesterone is available commercially with excellent quality control. Micronized progesterone is available commercially with excellent quality control. 100 mg is the usual dose. 100 mg is the usual dose. Take at bedtime on an empty stomach. Take at bedtime on an empty stomach. Progesterone cream not as well absorbed as oral progesterone. Progesterone cream not as well absorbed as oral progesterone.

83. 83 Key Points in Managing Menopausal Symptoms Establish that patient’s symptoms are related to menopause. Establish that patient’s symptoms are related to menopause. Assess the impact on quality of life. Assess the impact on quality of life. Determine what treatments patient has tried before (herbals, etc.) Determine what treatments patient has tried before (herbals, etc.) Look for any risk factors that make HT higher risk Look for any risk factors that make HT higher risk advanced age advanced age DVT DVT CV disease CV disease breast cancer (personal or first degree relatives) breast cancer (personal or first degree relatives) If HT is to be used, decide between oral and topical E2. If HT is to be used, decide between oral and topical E2. Decide which estrogen and which progesterone: lowest dose to control symptoms. Decide which estrogen and which progesterone: lowest dose to control symptoms.

84. 84 THE END THANK YOU. QUESTIONS ??

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