Menopause Review on Treatment Ivan Ying Department of Medicine, Schulich School of Medicine and Dentistry University of Western Ontario University of Western

Menopause Menopause Review on Review on TreatmentTreatment

Ivan YingIvan Ying

Department of Medicine, Schulich School of Medicine and Department of Medicine, Schulich School of Medicine and DentistryDentistry

University of Western OntarioUniversity of Western Ontario

Endocrinology RoundsEndocrinology Rounds

Wednesday January 27 2010Wednesday January 27 2010

OutlineOutline

IntroductionIntroduction Definitions, hormonal changes, Definitions, hormonal changes,

diagnosisdiagnosis SymptomsSymptoms TreatmentTreatment HRT and CancerHRT and Cancer Cardiovascular DiseaseCardiovascular Disease OsteoporosisOsteoporosis

Case Presentation 1Case Presentation 1 49 year old female presents because of 49 year old female presents because of

menopausal symptomsmenopausal symptoms PMH includes hypertension adequately treated PMH includes hypertension adequately treated

with Avaprowith Avapro 2 children aged 18 and 14 2 children aged 18 and 14 Non smoker, 1-2 glasses of wine a dayNon smoker, 1-2 glasses of wine a day Unable to tolerate hot flashes up to 4 to 5 times Unable to tolerate hot flashes up to 4 to 5 times

a daya day Poor sleepPoor sleep Random “panic attacks” associated with Random “panic attacks” associated with

sweating and intense anxietysweating and intense anxiety Sexual dysfunction (dyspareunia) causing strain Sexual dysfunction (dyspareunia) causing strain

on relationship with husbandon relationship with husband Still menstruating, but highly variable cycleStill menstruating, but highly variable cycle

Case Presentation 2Case Presentation 2 63 year old female presents because of 63 year old female presents because of

menopausal symptomsmenopausal symptoms PMH includes diabetes, HTN, PMH includes diabetes, HTN,

hypercholesteremia, CAD with stent, previous hypercholesteremia, CAD with stent, previous hysterectomyhysterectomy

Medications include metformin, glyburide Medications include metformin, glyburide Avapro, Crestor, ASA and PlavixAvapro, Crestor, ASA and Plavix

Family history significant for a sister with breast Family history significant for a sister with breast cancer at age 55cancer at age 55

Married, retired with no childrenMarried, retired with no children Amenorrhea since age 53, no previous HRTAmenorrhea since age 53, no previous HRT Unable to tolerate intense hot flashes 4 to 5 Unable to tolerate intense hot flashes 4 to 5

times a daytimes a day

IntroductionIntroduction

In 2009, largest demographic of “baby In 2009, largest demographic of “baby boomers” will reach the age of 50boomers” will reach the age of 50

Increased need for an understanding Increased need for an understanding and the symptoms and proper and the symptoms and proper management of menopausemanagement of menopause

Major health issues surrounding Major health issues surrounding menopause:menopause: Cardiovascular diseaseCardiovascular disease OsteoporosisOsteoporosis HRT and breast cancer riskHRT and breast cancer risk

IntroductionIntroduction What is menopause?What is menopause?

The cessation of menstrual periods, occurs secondary to The cessation of menstrual periods, occurs secondary to the genetically programmed loss of ovarian folliclesthe genetically programmed loss of ovarian follicles

Mean age of 51.4 in USMean age of 51.4 in US

Block, E, Acta Anat 1952; 14:108 and Gougeon, A, Contraception Fertile

Sexual 1984; 12:527.

IntroductionIntroduction STRAW (Stages of Reproductive Aging Workshop) Staging STRAW (Stages of Reproductive Aging Workshop) Staging

SystemSystem


During early menopausal transition, During early menopausal transition, changes in the hormones levels begin to changes in the hormones levels begin to occuroccur Decrease in number of follicles causes an Decrease in number of follicles causes an

overall rise in FSH, a preserved to high overall rise in FSH, a preserved to high estradiol level and low progesterone levelsestradiol level and low progesterone levels

Hormone levels highly variable during Hormone levels highly variable during menopause but ultimately leads to a menopause but ultimately leads to a lack of estradiol secretion from the lack of estradiol secretion from the ovary and a high FSH levelovary and a high FSH level



DiagnosisDiagnosis Clinical diagnosisClinical diagnosis 1 year of amenorrhea after the final 1 year of amenorrhea after the final

menstrual periodmenstrual period Routine measurement of hormone levels Routine measurement of hormone levels

(in particular FSH/estradiol) are not (in particular FSH/estradiol) are not recommended because of the high recommended because of the high variability during late menopausal variability during late menopausal transitiontransition

SymptomsSymptoms

Vasomotor symptomsVasomotor symptoms Hot flashesHot flashes SweatingSweating AnxietyAnxiety PalpitationsPalpitations

Urogenital symptomsUrogenital symptoms Vaginal DrynessVaginal Dryness Sexual DysfunctionSexual Dysfunction Incontinence?Incontinence?

SymptomsSymptoms

Other symptomsOther symptoms Sleep disturbanceSleep disturbance DepressionDepression Breast PainBreast Pain Menstrual migrainesMenstrual migraines Joint painJoint pain Skin changes Skin changes

TreatmentTreatment

Vasomotor SymptomsVasomotor Symptoms Lifestyle changes: regular exercise, weight Lifestyle changes: regular exercise, weight

management, smoking cessation and avoiding management, smoking cessation and avoiding known food triggers (EtOH, hot drinks) (Grade known food triggers (EtOH, hot drinks) (Grade IC)IC)

Non hormonal treatment (clonidine, SNRIs, Non hormonal treatment (clonidine, SNRIs, gabapentin) considered when HRT is gabapentin) considered when HRT is contraindicated or not wanted by patient contraindicated or not wanted by patient (Grade IB )(Grade IB )

HRT is the most effective medical management HRT is the most effective medical management of vasomotor symptoms (Grade IA)of vasomotor symptoms (Grade IA)

TreatmentTreatment Non-hormonal treatmentNon-hormonal treatment

Clonidine: some conflicting evidence for Clonidine: some conflicting evidence for efficacy, poorly tolerated because of side effect efficacy, poorly tolerated because of side effect profile (dry mouth, dizziness, constipation)profile (dry mouth, dizziness, constipation)

SNRIs: 2 relatively small RCTs showed it was SNRIs: 2 relatively small RCTs showed it was more effective than placebo, reducing more effective than placebo, reducing vasomotor symptoms by about ~35% with vasomotor symptoms by about ~35% with 75mg/day75mg/day

Gabapentin: Some evidence from small RCTs Gabapentin: Some evidence from small RCTs showing more effective than placebo, especially showing more effective than placebo, especially in tamoxifen induced vasomotor symptomsin tamoxifen induced vasomotor symptoms

TreatmentTreatment

Natural Health ProductsNatural Health Products Limited evidence for natural health products Limited evidence for natural health products

for treatment of moderate to severe vasomotor for treatment of moderate to severe vasomotor symptomssymptoms

Several systematic reviews showed no single Several systematic reviews showed no single NHP has convincingly showed effectiveness NHP has convincingly showed effectiveness for the treatment of vasomotor symptomsfor the treatment of vasomotor symptoms

RCT of HT versus soy, black cohosh and RCT of HT versus soy, black cohosh and multibotanicals showed only HT superior to multibotanicals showed only HT superior to placebo for symptom reliefplacebo for symptom relief1 1 (Herbal (Herbal Alternatives for Menopause Trial, HALT)Alternatives for Menopause Trial, HALT)

1Newton 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. AnnIntern Med 2006;145:869–79.

TreatmentTreatment

TreatmentTreatment

Vasomotor Vasomotor symptomssymptoms Progestin and low Progestin and low

dose oral dose oral contraception can contraception can be used for be used for menopausal menopausal symptoms in the symptoms in the menopausal menopausal transition phase transition phase (Grade IA)(Grade IA)

TreatmentTreatment

Urogenital Symptoms – Vaginal Urogenital Symptoms – Vaginal AtrophyAtrophy Vaginal lubricants (AstroglideVaginal lubricants (Astroglide©)©) for for

dyspareunia (Grade IIIC)dyspareunia (Grade IIIC) Vaginal moisturizer (ReplensVaginal moisturizer (Replens©)©) for for

vaginal dryness and dyspareunia (Grade vaginal dryness and dyspareunia (Grade IA)IA)

Estrogen cream, estradiol ring or tablets Estrogen cream, estradiol ring or tablets all effective for vaginal dryness (Grade all effective for vaginal dryness (Grade IA)IA)

TreatmentTreatment

Urogenital Symptoms - IncontinenceUrogenital Symptoms - Incontinence HRT HRT not not recommended for treatment of stress or recommended for treatment of stress or

urge incontinence (Grade IA)urge incontinence (Grade IA) HERS trial showed a 12% increased risk of weekly HERS trial showed a 12% increased risk of weekly

urge incontinence and a 15% increased risk of urge incontinence and a 15% increased risk of weekly stress incontinenceweekly stress incontinence11

2003 Cochrane review of 15 small trials showed 2003 Cochrane review of 15 small trials showed 50% of women treated with HRT reported 50% of women treated with HRT reported symptom improvement versus 25% of placebo symptom improvement versus 25% of placebo 22

Data is conflicting and pathophysiology of Data is conflicting and pathophysiology of estrogen and urinary symptoms is poorly estrogen and urinary symptoms is poorly understoodunderstood

1Grady 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;97:116–20.2Moehrer B, Hextall A, Jackson S. Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev 2003;2:CD001405.

TreatmentTreatment

Urogenital Symptoms – IncontinenceUrogenital Symptoms – Incontinence Stress: pelvic floor exercises, weight Stress: pelvic floor exercises, weight

loss, intravaginal pessariesloss, intravaginal pessaries Urge: lifestyle modification, Urge: lifestyle modification,

antimuscarinic therapyantimuscarinic therapy

Hormone Replacement Hormone Replacement TherapyTherapy

Recommendations:Recommendations: Low dose estrogen (0.3mg of conjugated Low dose estrogen (0.3mg of conjugated

estrogen or 0.5mg of estradiol), although estrogen or 0.5mg of estradiol), although 0.625mg conjugated estrogen used most 0.625mg conjugated estrogen used most oftenoften

Progestin therapy recommended for any Progestin therapy recommended for any patient receiving HRT and an intact uterus patient receiving HRT and an intact uterus (medroxyprogesterone acetate, MPA 2.5mg)(medroxyprogesterone acetate, MPA 2.5mg)

Consider estrogen therapy alone for Consider estrogen therapy alone for patients with hysterectomypatients with hysterectomy


What about breast cancer?What about breast cancer? Increased risk (RR:1.3) of EPT and Increased risk (RR:1.3) of EPT and

breast cancer after breast cancer after 5 years5 years of use of use WHI showed increased risk after 3 years in WHI showed increased risk after 3 years in

patients with previous HRT use, but no patients with previous HRT use, but no increased risk after 5 years in patients increased risk after 5 years in patients without previous HRTwithout previous HRT

Estrogen only arm showed no increased Estrogen only arm showed no increased risk, and in fact a non-significant decreased risk, and in fact a non-significant decreased risk of breast cancerrisk of breast cancer


What about breast cancer?What about breast cancer? RR of 1.023 for each year of HRT use, comparable RR of 1.023 for each year of HRT use, comparable

(RR: 1.028) increased risk for delayed menopause(RR: 1.028) increased risk for delayed menopause11

In comparison, a clinically significant In comparison, a clinically significant epidemiologically RR is 3, positive FmHx (RR:3), epidemiologically RR is 3, positive FmHx (RR:3), BRCA gene mutation (RR: 200)BRCA gene mutation (RR: 200)

““Million women study” showed that there was Million women study” showed that there was no no increased risk increased risk of breast cancer in all patients who of breast cancer in all patients who ceased HRT regardless of duration of treatment or ceased HRT regardless of duration of treatment or time since discontinuationtime since discontinuation22

Most women use HRT for symptomatic relief for Most women use HRT for symptomatic relief for less than 5 years, median duration of 2 yearsless than 5 years, median duration of 2 years11

1Collaborative 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;350:1047–592Beral V; for the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419–27.


What about breast cancer?What about breast cancer? Original study that sparked controversy Original study that sparked controversy

was the WHI that showed a HR of 1.24 was the WHI that showed a HR of 1.24 for developing breast cancer (after 5 for developing breast cancer (after 5 years)years)

Comparisons of other risk factors such Comparisons of other risk factors such as late menopause, excessive EtOH as late menopause, excessive EtOH consumption, first pregnancy after age consumption, first pregnancy after age 30, choosing not to breast feed carry 30, choosing not to breast feed carry comparable HR of about 1.3comparable HR of about 1.3


What about breast cancer?What about breast cancer? Family history: Patients on HRT with a Family history: Patients on HRT with a

family history of breast cancer family history of breast cancer are notare not at increased risk compared to baseline at increased risk compared to baseline risk from family historyrisk from family history

Personal history of breast cancer: Personal history of breast cancer: HABITs trial showed a higher rate of HABITs trial showed a higher rate of recurrence in the HRT armrecurrence in the HRT arm11 (22% (22% recurrence in the HRT arm and 8% in recurrence in the HRT arm and 8% in the control arm)the control arm)

1Holmberg 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.


What about breast cancer?What about breast cancer? SOGC recommends that “short term use of SOGC recommends that “short term use of

HRT for disruptive vasomotor symptoms HRT for disruptive vasomotor symptoms carries little appreciable risk for the carries little appreciable risk for the average woman entering menopause”average woman entering menopause”

Continue with regular mammography, Continue with regular mammography, periodic health exams including breast periodic health exams including breast examsexams

Focus on risk factor modification such as Focus on risk factor modification such as regular excercise, decrease EtOH, smoking regular excercise, decrease EtOH, smoking cessation, weight losscessation, weight loss

Cardiovascular DiseaseCardiovascular Disease

Observational studies originally Observational studies originally pointed towards the cardioprotective pointed towards the cardioprotective effects of HRTeffects of HRT

WHI originally reported an increased WHI originally reported an increased risk of MI and stroke for patients on risk of MI and stroke for patients on EPTEPT Follow-up analysis of the data showed no Follow-up analysis of the data showed no

statistically significant increased risk of statistically significant increased risk of MI/stroke but an increased risk in the first MI/stroke but an increased risk in the first year of initiating therapyyear of initiating therapy


Risk of CVD and HRT appears to be Risk of CVD and HRT appears to be age dependentage dependent WHI and HERS showed WHI and HERS showed increased riskincreased risk

of CVD in the first year of treatment in of CVD in the first year of treatment in older women (average age in WHI was older women (average age in WHI was 13 years after menopause)13 years after menopause)

Nurses Health Study found a Nurses Health Study found a decreaseddecreased risk of CVD in women starting HRT risk of CVD in women starting HRT under the age of 55under the age of 55


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

Cerebrovascular DiseaseCerebrovascular Disease

Meta-analysis of large RCTs Meta-analysis of large RCTs (including HERS and WHI) points (including HERS and WHI) points towards a possible increased risk of towards a possible increased risk of ischemic stroke (but not TIA or ischemic stroke (but not TIA or hemorrhagic stroke) (RR ~1.3)hemorrhagic stroke) (RR ~1.3)

Unlike cardiovascular disease, risk Unlike cardiovascular disease, risk does not seem to be related to does not seem to be related to timing of HRTtiming of HRT


Mainstay of treatment is known risk Mainstay of treatment is known risk factor modification: lifestyle, factor modification: lifestyle, hypertension, diabetes, hypertension, diabetes, hypercholesterolemiahypercholesterolemia

HRT should not be used for the sole HRT should not be used for the sole purpose of prevent CVD (Grade IA)purpose of prevent CVD (Grade IA)

Initiating HRT in older post-menopausal Initiating HRT in older post-menopausal women should be done with counselling women should be done with counselling and caution, low dose estrogen preferred and caution, low dose estrogen preferred (Grade IA)(Grade IA)

OsteoporosisOsteoporosis

Mainstay treatment is adequate Mainstay treatment is adequate calcium, vitamin D and bisphosphonate calcium, vitamin D and bisphosphonate therapy for those at high risktherapy for those at high risk

What about HRT?What about HRT? Estrogen is known to significantly Estrogen is known to significantly

increase osteoblast activityincrease osteoblast activity WHI showed a ~35% reduction in WHI showed a ~35% reduction in

fractures in the estrogen only arm and fractures in the estrogen only arm and ~24% reduction in the EPT arm~24% reduction in the EPT arm


What about low or ultra low dose What about low or ultra low dose estrogen?estrogen? 0.3mg of conjugated estrogen of 0.5mg 0.3mg of conjugated estrogen of 0.5mg

of estradiol considered “low dose” and of estradiol considered “low dose” and 0.15mg conjugated estrogen considered 0.15mg conjugated estrogen considered ultra low doseultra low dose

RCTs have shown low dose helps RCTs have shown low dose helps prevent osteoporosis, but no RCTs prevent osteoporosis, but no RCTs showing if it reduces fracture riskshowing if it reduces fracture risk


Recommendations:Recommendations: HRT should be used for menopausal HRT should be used for menopausal

symptoms and is a reasonable choice symptoms and is a reasonable choice for the prevention of bone loss and for the prevention of bone loss and fracture (Grade IA)fracture (Grade IA)

Low dose and UL dose estrogen can be Low dose and UL dose estrogen can be used for menopausal symptoms, no used for menopausal symptoms, no evidence for reduction of fracture risk evidence for reduction of fracture risk (Grade IA)(Grade IA)

Mood and Cognition Mood and Cognition

Estrogen can be used to augment Estrogen can be used to augment the effect of traditional anti-the effect of traditional anti-depressants in perimenopausal depressants in perimenopausal women may also be used alone to women may also be used alone to treat depressive symptoms (Grade treat depressive symptoms (Grade IA)IA)

Estrogen should not be used for the Estrogen should not be used for the primary or secondary prevention of primary or secondary prevention of dementia (Grade IB)dementia (Grade IB)

Back to Case 1Back to Case 1 49 year old female presents to your office 49 year old female presents to your office

complaining of menopausal symptomscomplaining of menopausal symptoms PMH includes hypertension adequately treated PMH includes hypertension adequately treated

with Avaprowith Avapro 2 children aged 18 and 14 (born when she was 2 children aged 18 and 14 (born when she was

31 and 35)31 and 35) Non smoker, 1-2 glasses of wine a dayNon smoker, 1-2 glasses of wine a day Hot flashes on almost daily basisHot flashes on almost daily basis Poor sleepPoor sleep Random “panic attacks” associated with Random “panic attacks” associated with

sweating and intense anxietysweating and intense anxiety Sexual dysfunction (dyspareunia) causing strain Sexual dysfunction (dyspareunia) causing strain

on relationship with husbandon relationship with husband Still menstruating, but highly variable cycleStill menstruating, but highly variable cycle

Back to the Case 1Back to the Case 1 49 in menopausal transition49 in menopausal transition

Vasomotor symptoms: Lifestyle modification; HRT or OCP Vasomotor symptoms: Lifestyle modification; HRT or OCP both reasonable options to help control her symptoms, if HRT both reasonable options to help control her symptoms, if HRT is chosen low dose estrogen with progestin is recommendedis chosen low dose estrogen with progestin is recommended

Urogenital symptoms: Local estrogen through a ring or Urogenital symptoms: Local estrogen through a ring or cream, as well non hormonal treatment such as lubricantscream, as well non hormonal treatment such as lubricants

Breast cancer: increased risk of breast cancer is considered Breast cancer: increased risk of breast cancer is considered minimal, recommend short term use (<5 years), risk is back minimal, recommend short term use (<5 years), risk is back to baseline soon after cessation of therapyto baseline soon after cessation of therapy

Cardiovascular disease: Focus on traditional risk factor Cardiovascular disease: Focus on traditional risk factor modification, but HRT at this stage of menopause may be modification, but HRT at this stage of menopause may be cardio protectivecardio protective

Osteoporosis: Adequate calcium and vitamin D intake, Osteoporosis: Adequate calcium and vitamin D intake, bisphosphonates if indicated; HRT considered protective but bisphosphonates if indicated; HRT considered protective but not used as primary treatmentnot used as primary treatment

Back to Case 2Back to Case 2 63 year old female presents because of 63 year old female presents because of

menopausal symptomsmenopausal symptoms PMH includes diabetes, HTN, PMH includes diabetes, HTN,

hypercholesteremia, CAD with stent, previous hypercholesteremia, CAD with stent, previous hysterectomyhysterectomy

Medications include metformin, glyburide Medications include metformin, glyburide Avapro, Crestor, ASA and PlavixAvapro, Crestor, ASA and Plavix

Family history significant for a sister with breast Family history significant for a sister with breast cancer at age 55cancer at age 55

Married, retired with no childrenMarried, retired with no children Amenorrhea since age 53, no previous HRTAmenorrhea since age 53, no previous HRT Unable to tolerate intense hot flashes 4 to 5 Unable to tolerate intense hot flashes 4 to 5

times a daytimes a day

Back to Case 2Back to Case 2

63 year old female 10 years post menopause63 year old female 10 years post menopause HRT still a viable option because of severe HRT still a viable option because of severe

vasomotor symptomsvasomotor symptoms If HRT is chosen, should be given unopposed If HRT is chosen, should be given unopposed

estrogen (previous hysterectomy, may not estrogen (previous hysterectomy, may not increase breast cancer risk)increase breast cancer risk)

HRT should not increase baseline risk given HRT should not increase baseline risk given family historyfamily history

Risk of CVD should be a serious point of Risk of CVD should be a serious point of discussion, evidence clearly points to an increased discussion, evidence clearly points to an increased risk of MI and stroke in the first year in this risk of MI and stroke in the first year in this populationpopulation

Questions? Comments?Questions? Comments?

Documents

Menopause Review on Treatment Ivan Ying Department of Medicine, Schulich School of Medicine and Dentistry University of Western Ontario University of Western