Menopause 2014

Janet Pregler, M.D., FACP Director, Iris Cantor-UCLA Women’s Health Center David Geffen School of Medicine University of California, Los Angeles

Disclosure of Financial Relationships Janet Pregler, M.D., FACP Have no relationships with any proprietary entity producing health care goods or services consumed by or used on patients.

Menopause Update • What new information is available about symptoms during the menopause transition? • What are effective hormonal and non-hormonal approaches to the treatment of vasomotor symptoms and vaginal atrophy? What is the role of new medications approved for these indications by the FDA in the last year? • Do different hormonal preparations, including “bioidentical hormones” have different risks or benefits? • What is the role of complementary and alternative medicine in the treatment of menopausal symptoms?

Presentation of a Case

A.R. is a 52 year old woman who presents with complaints of hot flashes, irritability, and diffuse muscle aches after stopping her HT when she heard it causes strokes. However, a friend who lives in San Diego gave her a copy of a “Harvard Women’s Health Watch” that suggests that since she has a high risk of heart disease, she should take HT. The same friend gave her a local newspaper article quoting famous gynecologists who said the same thing. She asks for your advice.

Presentation of a Case

Allergies: None PMHx/PSHx: s/p hysterectomy for fibroids, age 40, ovaries intact Medications: None Family History: Mother died of an MI at age 55, father died of an MI at 57. One sister, healthy. Social History: Married, no children. Works as a lawyer. Has smoked one pack per day for 35 years. Does not drink alcohol. No regular exercise. Eats few fruits and vegetables. ROS: Vaginal dryness uncomfortable during sex.

Presentation of a Case

PE: BMI= 27 BP= 139/89 HR= 80, reg.RR=12 T= 37 C, remainder of the exam unremarkable, except vaginal atrophy.

Labs: TC 244 mg/dL LDL 159 mg/dL HDL 35 mg/dL TG 240 mg/dL, Fasting glucose= 109 mg/dL, Mammogram, Pap smear, Colonoscopy WNL

Estimated 10 year ASCVD risk 9.7%

Presentation of a Case When you return to the room after examining her, she presents you with a list of additional questions, including: • I am having trouble with my memory, is it from my menopause? • My friend has depression, is it because she is in menopause? • If I don’t take estrogen, will my skin look old? • Does estrogen cause breast cancer? • If I take estrogen, is bioidentical safer? • I saw on television that there’s a pill for vaginal dryness, should I take it?

Menopause New Information on Natural History and Associated Symptoms

Epidemiology of Vasomotor Symptoms • African American and Latina patients may be more likely to experience vasomotor symptoms, and experience them for longer • Higher BMI is associated with a higher likelihood of vasomotor symptoms • Smokers enter the menopausal transition earlier, and are more likely to experience hot flashes

Freeman Menopause 2014; Gold Am J Pub Health 2006

Meta-analysis of Prevalence of Vasomotor Symptoms by Time from Menopause Polti JGIM 2008

60 % of 50 Women 40 with 30 Vasomotor 20 Symptoms 10 0 -2 yrs

+1 yr

+ 5 yrs

+ 12 yrs

Percent of African American and White Women with Moderate to Severe Hot Flashes: Penn Ovarian Aging Study Freeman Menopause 2014 50 45 40 35

% 30 25 20 15 10 5 0

-10 yrs -5 yrs

-1 yr

Final +1 yr Menses

+ 5 yr

+10 yr

Natural History of Menopause Systemic symptoms of menopause are not all associated with the degree of vasomotor symptoms

•

•

Sleep disturbance occurs in women without vasomotor symptoms

•

Depression is more common during the menopause transition

•

Cognitive changes reported by some women at the time of menopause relate to the stage of menopause, and improve when the menopause transition is completed

Greendale Neurology 2009; 72: 1850; Bromberger Psychological Medicine 2011 41:1879; Kravtiz Obstet Gynecol Clin N Am 2011 38:567

Study of Women’s Health Across the Nation (SWAN): Major Depression Risk Over 10 Years of Follow-up by Menopausal Status or Age Not adjusted for VMS

Adjusted for VMS

Adjusted for prior major depression, use of psychotropic medications, life events, BMI

4.5 4

RR 3.5 3 2.5 2 1.5

*Trend toward decreasing RR more than 2 yrs after menopause

1 0.5 0

Peri-menopause

Post-menopause*

Age

Adapted from: Bromberger Psychological Medicine 2011 41:1879

Perimenopause is Bad for Your Brain, but You Bounce Back in Postmenopause I

62

60 Premenopaus e

58

Early perimenopaus e

Score

Late perimenopaus e Pos t menopaus e

56

54 4

5

6 Years

7

8

Illustrations of adjusted trajectories of Symbol Digit Modalities Test scores in each menopause transition (MT) stage, assuming MT stage fixed for 4 years Source: Greendale Neurology 2009; 72: 1850

Hormone Treatment Major Chronic Disease Effects

Treatment of Menopausal Symptoms: Hormone Therapy • Hormone therapy remains the most effective treatment for vasomotor symptoms, with a reduction in symptoms of 80-90% • Overall risks of hormone therapy are low for otherwise healthy women at the time of menopause • For women with a uterus, estrogen without a progestin increases the risk of endometrial cancer, and is not recommended in most cases • Both estrogen and estrogen + progestin increased stroke risk in WHI, whether they were started close to menopause or not. Based on this, long term use of hormones for chronic disease prevention is not recommended

Menopause Hormone Therapy Risk-Benefit Balance 2014 Symptoms/Side Effects

Risks Breast/Bleeding Side Effects Urinary incontinence Kidney stones Gallstones

Benefits (all while on therapy) Vasomotor Symptoms Vaginal Atrophy ?Skin Preservation ?Depression

ACOG Obstet Gynecol 2004, Chlebowski JAMA 2008; Chlebowski JAMA 2010; Maalouf Arch Intern Med 2010; Manson JAMA 2013; Grady JAMA 2002

Estrogen + Progestin Risk-Benefit Balance 2014 Major Chronic Disease Outcomes Risks Stroke Breast Cancer (includes increased breast cancer mortality, risk persisted after discontinuation of treatment) CHD (at initiation, older women/existing CHD) Venous thrombosis Dementia (women over 65 years) Pancreatitis ?Ovarian Cancer

Benefits Osteoporosis Diabetes (taking therapy)

ACOG Task Force for Hormone Therapy Obstet Gynecol 2004 ; Chlebowski JAMA 2008; Chlebowski JAMA 2010; Manson JAMA 2013; Grady JAMA 2002

Estrogen Alone Risk-Benefit Balance 2014 Major Chronic Disease Outcomes Risks (while on therapy) Stroke Dementia (women over 65 years- trend, trial stopped early) Venous thrombosis Endometrial Hyperplasia/Cancer Pancreatitis ?Ovarian Cancer

Benefits Breast Cancer Incidence (5-6 yrs of therapy, 13 yrs of follow-up) Osteoporosis (taking therapy) Diabetes (taking therapy)

ACOG Task Force for Hormone Therapy, Obstet Gynecol 2004; Chlebowski JAMA 2011; Manson JAMA 2013; U.S. FDA

Principles of Hormone Treatment • Very important to add progestin in women with a uterus • In the PEPI trial, 34% of women on unopposed estrogen developed advanced hyperplasia after 3 years of treatment

Writing Group for the PEPI trial. JAMA 1996

Why avoid estrogen only therapy in breast cancer survivors? Effect on existing tumor may be different than prevention: Data from WHI • Invasive breast cancers in women assigned to CEE were larger (1.8 cm compared to 1.5 cm, p=.03) • Invasive breast cancers in women assigned to CEE tended to be node positive (36% vs. 23%, p=.07)

Stefanick JAMA 2006;295:1647

Nurses Health Study cohort study: Women who have oophorectomy compared with ovarian conservation with hysterectomy for benign disease have higher mortality: Is it hormones, selection bias, or both? 1.6 1.4

* *

Mortality

1.2 1 0.8

HR

0.6 0.4 0.2 0

< 50 yrs 50-59 yrs 60 yrs +

Parker Obstet Gyecol 2013

No HT

HT

* Statistically Significant

Nurses Health Study cohort study: Causes of death for women who had oophorectomy compared to ovarian conservation during hysterectomy for benign disease 1.6 1.4

* * *

*

1.2 1 0.8

Hazard Ratio for Mortality

0.6 0.4 0.2 0

* Statistically Breast Lung CA CA

Colon CA

Parker Obstet Gynecol 2013

Total CA

CVD

Significant

Guidelines about Hormone Therapy for Chronic Disease Prevention • American College of Obstetricians and Gynecologists (ACOG) • “Menopausal HT should not be used for the primary or secondary prevention of CHD at the present time.” • “Recent evidence suggests that women in early menopause who are in good cardiovascular health are at low risk of adverse cardiac outcomes and should be considered candidates (for HT) for relief of menopausal symptoms.” • U.S. Preventative Services Task Force (USPSTF) • The USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women (Grade D: Evidence of Harm) • The USPSTF recommends against the use of estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy (Grade D: Evidence of Harm) ACOG Committee Opinion Hormone Therapy and Heart Disease Obstet Gynecol 2013; USPSTF October 2012

Global Events per 10,000 Women Per Year: CHD, Invasive Breast, Colon, and Endometrial Cancer, Hip Fracture, PE, All Cause Mortality Manson JAMA 2013

Note: In WHI, all women assigned to CEE alone were s/p hysterectomy

50-59 y

60-69 y 70-79 y

Estrogen Therapy in Postmenopausal Women and Skin Changes 5 4.5 4

Investigator Global 3.5 Assessment 3 of 2.5 Wrinkling

Placebo 1 mg NA/ 10 ug EE

2

1.5 1 Baseline

Phillips J Am Acad Dermatol 2008

48 Weeks

No statistically significant difference

Hormone Treatment Are Some Formulations Safer/Better?

FDA Takes Action Against Compounded Hormone Therapy Drugs (“Bioidenticals”) • Risks of compounded bioidenticals unknown • No evidence of greater safety, efficacy • Estriol not FDA approved • Saliva testing to determine hormone levels is inaccurate • Hormone levels fluctuate

Source: FDA Press Release, January 9, 2008

American College of Obstetricians and Gynecologists Committee Opinion August 2012 “Not only is evidence lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy, but these claims also pose the additional risks of variable purity and potency and lack efficacy and safety data”

• Under and overdosage are of concern, eg. endometrial hyperplasia and cancer are a concern with untested/unreliable doses of estrogen and progestins • Estradiol and micronized progesterone are available in proven formulations, and are preferred given available data

ACOG Committee Opinion #532, August 2012

Breast Cancers and Different HT Formulations

“Million Woman Study Shows Breast Cancer Risk” • Prospective cohort study in Britain • For CURRENT USERS, increased incidence of breast CA for both E alone (RR = 1.3) and E + P (RR = 2.0) • Increased for pills, patches, implants, continuous, and sequential regimens

Beral Million Women Study Coordinators. Lancet 2003;362:419

ACOG Committee Opinion 2013: Postmenopausal Estrogen Therapy: Route of Administration and Risk of Venous Thromboembolism

• Cohort studies of transdermal estrogen in postmenopausal women have not shown increased risk of venous thromboembolism compared to non-users • Some have postulated that this is because transdermal ET does not effect prothrombotic factors and may have beneficial effects on proinflammatory markers

Things to consider: • Multiple cohort studies of Ortho Evra (R) contraceptive patch have shown increased thrombotic risk, currently Ortho Evra (R) contraceptive patch carries a black box warning for thrombotic risk, which is attributed to different pharmacokinetics of estrogen with patch delivery (lower peaks but higher average levels) Bottom line: Clinicians are free to counsel that transdermal delivery is preferred if that is their interpretation of the data, but FDA does not recognize that patches are safer than oral forms, and use of any form of estrogen in women at high risk for venous thromboembolism is relatively contraindicated according to FDA ACOG Committee Opinion #556 April 2013

Newly FDA approved for Treatment of Vasomotor Symptoms

• Conjugated equine estrogens/bazedoxifene (Duavee ® ) • Estrogen with new SERM, approved by FDA in 2013 for treatment of vasomotor symptoms and prevention of osteoporosis in women with a uterus • Boxed warning: risk of endometrial cancer, stroke, DVT, dementia, do not use for prevention of dementia OR CHD. Also, do not use if breast or other estrogen-dependent cancer, pregnancy. • 24 months of endometrial safety data, over 24 months increased hip and spine BMD, effect on hot flashes similar range to estrogen • Studies lacked power (6200 patients over max 2 years) to adequately assess stroke and DVT, but increased risk known for HT and other SERMS; breast cancer effects unknown • About 15% of patients spotting at one year • Dose CEE 0.45 mg/bazedoxifene 20 mg, one po daily; given limited data, an alternative to traditional estrogen plus progestin therapy for hot flashes, but not proven to be safer/better than estrogen plus progestin although it might be FDA 2013

Vasomotor symptoms Non-Hormonal Treatment

Nonhormonal Pharmaceuticals for Hot Flashes More Effective Than Placebo in Randomized, Controlled Trials: Lowest Effective Dose, nonFDA Approved Use Unless Noted • Venlafaxine XR 75 mg/d (37.5 mg/d also effective) • Desvenlafaxine 100 mg/d • Paroxetine CR 12.5 mg/d; Paroxetine 10 mg/d; Paroxetine 7.5 mg/ day (FDA approved 2013, Brisdelle (R) ) • Fluoxetine 20 mg/d • Sertraline 50 mg/d • Citalopram 20 mg/d • Escitalopram 10-20 mg/d • Note: There is evidence that SSRIs (paroxetine) may interfere with tamoxifen metabolism, rendering it less effective. • Gabapentin 300 mg tid (up to 2700 mg/d may increase relief) • Pregabalin 75 mg bid • Clonidine 0.1 mg/d Loprinzi Lancet. Guttuso Obstet Gynecol. Loprinzi J Clin Oncol. Stearns JAMA. Kimmick The Breast Journal 2006 Pandya Ann Intern Med. Sterns J Clin Oncol 2005 Gordon Menopause 2006, Speroff Obstet Gynecol 2008; Kalay Menopause 2007; Freeman JAMA 2011; Kelly BMJ 2010; FDA 2013

Escitalopram for Hot Flashes in Healthy Menopausal Women: A Randomized Controlled Trial Freeman JAMA 2011

10 8

*

Mean # of 6 Hot Flashes 4 2 0 Baseline

Escitalopram

*Statistically fewer hot flashes than placebo

Placebo

“Back to the Future”:

Anxiolytics for Hot Flash-Related Sleep Disturbance 80 70 60

*

50

Zolpidem 10 mg qhs Placebo

40

% indicating better sleep

30 20 10 0 Week Week Week Week 1 2 3 4

*p < .001 for each week, improvement in sleep-related daytime functioning p 5 mm endometrial thickness

FDA 2013

Proliferative Endometrium

Uterine polyps

Treatment of Vaginal Atrophy • Lubricants • Eg, KY Jelly ®, Astroglide ®, etc, as needed or on a regular basis • Replens ® on a regular basis • Local hormone therapies- more effective/good safety data • Estring ® insert one q 12 weeks • Vagifem ® 10 ug nightly x 14 d then biw • “Low dose” topical estrogen • Cochrane review found ? more risk of endometrial hyperplasia, Premarin ® vaginal cream .5 gm biw studied for one year • Systemic dose therapies- use only if other treatments fail or if using systemic dose estrogen for vasomotor symptoms • Systemic dose estrogen delivered vaginally (cream or Femring ®), use progestin if patient has a uterus • Ospemiphene (SERM): If patient has a uterus, concern for endometrial hyperplasia/cancer with longer use • Other systemic dose hormones Cochrane Database Syst Rev. 2006, 2010; FDA 2013