Menopause / Hormone Replacement Therapy JENNIFER KEEHBAUCH, MD PROGRAM DIRECTOR WOMEN S HEALTH FELLOWSHIP FLORIDA HOSPITAL

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1 Menopause / Hormone Replacement Therapy JENNIFER KEEHBAUCH, MD PROGRAM DIRECTOR WOMEN S HEALTH FELLOWSHIP FLORIDA HOSPITAL

2 Disclosure Statement Jennifer Keehbauch, MD is a trainer for Merck Nexplanon

3 Learning Objectives 1. Counsel post-menopausal women regarding the risks and benefits of pharmacologic and non-pharmacologic options for the relief of menopausal symptoms. 2. Assess patients current use of nutritional, herbal or dietary supplements for the relief of menopausal symptoms and provide counseling to encourage safe and effective use. 3. Educate patients regarding their increased risk of coronary artery disease and osteoporosis following menopause and how to take preventive measures, including diet and exercise. 4. Differentiate specific issues, disease processes, and treatments based on ethnicity, gender and genetics.

4 Terminology Menopause is a natural event defined as 12 months of amenorrhea with no obvious pathologic cause. Perimenopause is the lay term encompassing the menopause transition and the first 12 months after the final menstrual period (FMP). Estrogen Therapy (ET) is unopposed estrogen for postmenopausal women without a uterus. Estrogen-Progestogen Therapy (EPT) is a combination of estrogen and progestogen (either progestin or progesterone). Hormone Therapy (HT) encompasses both ET and EPT. 4

5 Stages of Menopause Highest prevalence of menopausal symptoms Menopause. Journal of Clinical Endocrinology and Metabolism, Executive Summary of the Stages of Reproductive, April 2012, 97(4): ,

6 What is the most common age range for US women to experience menopause? A. Age 38 to 45 years B. Age 55 to 60 years C. Age 52 to 59 years D. Age 45 to 55 years E. Age 42 to 48 years

7 Menopause would most likely occur at an earlier than average age in which woman? A. One who smokes 2 packs of cigarettes per day B. One who has had 3 children C. One who has a 10-year history of oral contraceptive use D. One whose mother entered menopause at age 56 E. One whose body mass index is 30 kg/m2

8 Risk factors for Earlier Menopause Smoking (up to 2 years) Nulliparous Hysterectomy Fragile X carrier Autoimmune disorder Living at high altitude Exposure to chemo/radiation

9 Premature or Early Menopause Menopause before age years Less than 1% of women Etiologies: Most commonly idiopathic Fragile X Radiation Exposure: > 500 rads Treatment: HRT until age 51 for bone preservation BMJ 2012;344:e763

10 Decreasing Estrogen Levels Thermoregulatory set point lowered Serotonin levels decreased Thinning of vaginal epithelium Thinning of urethral epithelium Decreased blood flow to vagina/vulva Psychiatr Clin N Am 33 (2010)

11 Symptoms of Menopause Physical Changes Vasomotor symptoms Vaginal dryness Sexual dysfunction Urinary incontinence Bone loss Skin changes Intangible Changes Depression Breast Pain Common in early menopausal transition Sleep disturbances Memory loss

12 Racial/Ethnic Differences in Menopausal Symptoms Caucasian women report more psychosomatic symptoms African American women report more VMS Japanese and Chinese women report fewer symptoms overall Soc Sci Med 2001;52(3):

13 Diagnosis History: 12 consecutive months of amenorrhea Average age 51 Diagnostic labs not indicated

14 A 51-year-old woman has frequent and distressing hot flushes that interfere with her work and sleep, and vaginal dryness that makes sexual intercourse with her husband uncomfortable. She is otherwise healthy. How should her case be managed?

15 Menopause Treatment Discussion Individualization: incorporate the woman s health and QOL priorities personal risk for VTE, CHD, CVA, and breast ca Hormone therapy (HT) Non-hormone therapy Bioidentical HT

16 1966 With Hormone Therapy, a woman s breasts and genital organs will not shrivel. She will be much more pleasant to live with and will not become dull and unattractive. 16

17 The Evidence in the 1990 s Can start HRT at any time: Cardioprotective Delayed Alzheimers Reduced Colon Cancer Prevented Macular degeneration

18 USPSTF Recommendation USPSTF recommends against routine use of Estrogen or Combined HT for prevention of chronic conditions (D) Based on meta-analysis of 9 studies, primarily from: the Women's Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS) LOE:1A Ann Intern Med 2012

19 USPSTF Absolute Numbers per 10,000 users per year Combined HT Estrogen Only Fractures 46 less 56 less Breast cancer 8 more none Stroke 9 more 11 more DVT/PE 21 more 7 more Dementia 22 more none Death none 2 less

20 Criticism of HERS and WHI trials HERS average age 67, with known CHD 75% new users to hormones WHI average age 63 36% on anti-hypertensives, 20% on aspirin Both trials used mg conjugated estrogens alone or with 2.5 mg medroxyprogesterone acetate per day for less than 5 years JAMA 1998; 280: JAMA 2002;288: Hum. Reprod. (2003) 18 (10):

21 Effect of HRT on CV Events in Recently Post- Menopausal Women 10-year randomization on 2016 healthy women with mean age of 49.7 Reduced risk of death with up to 10 years use (RR 0.61 p=0.02) NO increase risk of thromboembolism or breast cancer (RR 0.90, p=0.72) or other cancers (RR1.21, p=0.35) BMJ e763

22 Summary of Evidence for All-Cause Mortality RR CI Meta-analysis of Observational data HERS WHI (ERT) WHI (HRT) DOPS

23 Vasomotor Symptoms

24 An App for Menopause The North American Menopause Society (NAMS) has released a free mobile app For Physicians or Patients Input patient data and preferences and it recommends hormonal and nonhormonal options

25 Management of VMS HRT is the most effective treatment for severe hot flushes (LOE=1A) Transdermal or transvaginal route should be considered (LOE=1B) Therapy with progestins, SSRIs, or gabapentin is suggested as alternatives

26 Complementary and Alternative Medicine (CAM) 80% of women in the SWAN study used CAM Common forms of CAM: vitamins, dong quai, soy, black cohosh, red ginger, acupuncture, and relaxation techniques Menopause Jul-Aug;14(4):612-23

27 Contraindications for HRT Unexplained vaginal bleeding Hormone sensitive cancers Past history of thromboembolus Hypertriglyceridemia Chronic liver disease Active or Recent Stroke or AMI

28 What is the most prevalent menopausal symptom reported by US women? A. Genitourinary atrophy B. Depression C. Insomnia D. Hot flush E. Headache

29 Vasomotor Symptoms Moderate to severe VMS affects 50% of women VMS typically last 7.4 years Range years Lasts longer in African American women (10.1 yrs) Symptoms persist in 10-15% women JAMA Inter Med 2015;175(4): NEJM 2006;355:

30 North American Menopause Society (NAMS) Recommends Lifestyle Changes Avoid Triggers: spicy food, alcohol, caffeine Keeping core body temperature cool Lower AC, light clothing, fan at night Weight loss Exercise, relaxation therapy & stress management alone not effective NAMS Menopause Practice, A Clinician s Guide 2010; Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD006108

31 Candidates for Nonhormonal Therapies Treatment Naïve OTC remedy failures or minimal effect Cannot or choose to not use HT Desire or need to discontinue HT

32 Which of the following is effective for post-menopausal hot flushes? A. Dong Quai B. Venlafaxine C. Soy D. Clonidine E. St John s Wort

33 Treatment of Hot Flushes Most effective Effective Possibly Effective NOT effective or not indicated Estrogen (85-95%) Venlafaxine (60-65%) Progesterone Paroxetine Gabapentin Clonidine Black Cohosh Dong Quai SERMS(NI) Phytoestrogens (soy) Red Clover St John s Wort Obstet Gynecol 2014 Jan;123(1);

34 Which of the following conditions is an absolute contraindication to hormone replacement therapy? A. Poorly controlled hypertension B. Undiagnosed genital bleeding C. History of thromboembolic disease D. Migraines E. Gallbladder disease

35 Estrogen-Only Preparations for Women Without a UTERUS Standard doses: mg conjugated equine est 1 mg micronized 17-beta estradiol 50 mcg/day transdermal 17-β-est 1.25 mg piperazine estrone sulfate Consider starting at lower doses (0.3 mg conjugated estrogens or 0.5 mg estradiol) Estrogen Medication Route Conjugated Premarin PO, Vaginal Synthetic Enjuvia PO Esterified Menest PO 17-β Estradiol Estrace Climara Vivelle/dot Estrogel Divigel Evamist Depo-Estradiol PO/Vaginal Patch Patch Gel Gel Spray Injectable

36 Estrogen-Progestin Combinations for Women Who Have a Uterus Estrogen/Progestin Medication Route Ethinyl Estradiol & Norethinedrone 17-β Estradiol & Norethinedrone Femhrt, Jinteli, Combipatch Activella, Lopreeza, Mimvey PO Transdermal 17-β & Levonorgesterol Climara Pro Transdermal CEE/Medroxyprogesterone Premphase Prempro Estrogen/SERM Medication Route CEE/Bazedoxifene Duavee PO PO PO PO

37 Role of Transdermals Transdermal estrogen may have a lower risk of VTE and stroke Doesn t increase triglycerides or HDL Have less nausea May be preferred for women with: Migraines Gallbadder disease BMJ 2012;344:e763 Climacteric: J of InternMeno Soc: 2010;13:

38 Perimenopausal Women Low dose OCPs can be used in lean, healthy, non-smoking women Benefits: Decrease vasomotor symptoms Restore predictable bleeding pattern Enhance BMD Once 50-yo, discuss stopping OCP consider changing to postmenopausal regimen if necessary for sx (practice-based) BMJ 2012;344:e763

39 Summary: HRT for Hot Flashes The lowest effective dose of ET should be prescribed Duration of treatment dictated by clinical needs and safety monitoring Stopping or tapering of HRT will cause recurrence of symptoms in 50% of women Vaginal bleeding within 6 months of initiating HRT does not need investigation BMJ 2012;344:e763.

40 Vaginal Symptoms

41 Esrogen Treatment Most Effective for Vaginal Symptoms (1B) Local vaginal therapy highly effective for treating atrophy Success rates > 80% Controversial in women with hx of breast cancer NO concomitant progestogen therapy required But no long-term safety trials Formulations vary: Beware FEMring (estradiol acetate) delivers systemic dose 2012 Mar;19(3):

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43 Atrophic Vaginitis Treatment Options Creams Ring Vagitories Vaginal Tablets Premarin Conjugated equine estrogens (CEE) Estrace Estradiol cream Retail ~ $300 Estring Releases estradiol in a consistent manner over 90 days Retail ~ $300 Ortho Gynest Vaginal estriol suppositories Not currently available in the United States Vagifem (Estradiol) vaginal estrogen tablet Retail ~ $200

44 Affordable Topical Estrogen ~ $4 Vaginal Estrogen needed is ~ 0.1mg Can use compounded doses at Walgreens or 0.15 mg/gm Can use ¼ tab of Estrace 0.5 mg (0.125 mg) PV qhs for 2 weeks, then 1-3 times a week

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46 SERM for Vulvar Vaginal Atrophy Ospemifene (Osphena) 60 mg po daily Selectively stimulates vaginal tissue, bone Does not stimulate endometrium Does not stimulate breast tissue Side effects may include hot flashes and thrombosis Prescriber's Letter. June 2013; 29 Int J Womens Health Sep 25;5:

47 Non-Hormonal Treatment Options for Vaginal Symptoms Lubricants: Water-based: Slippery Stuff, Astroglide, KY Jelly Silicon-based: ID millennium, PINK Oil-based: Elegance Women s Lubricant (not compatible with condom) Moisturizers: intended for use one or more times per week not just during sexual activity Replens, Me Again, Vagisil Feminine Moisturizer, Feminease, KY SILK-E

48 Does testosterone increase libido in postmenopausal women? Transdermal Testosterone increases libido in women (LOE=1b) No medication approved by the FDA Canada/UK approved 300 mcg patch daily Long-term safety unknown We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable. Endocrine Society J Clin Endocrinol Metab Oct;99(10): ; AAFP Essentials 2012;

49 Hormone Therapy for Sexual Function in Menopause HT with estrogen alone or combined estrogen/progesterone produces small to moderate improvement in symptomatic women within 5 years of menopause Unable to assess effect of SERMS or synthetic steroids Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD

50 Filbanserin (Addyi) pink Viagra To be able to prescribe Addyi, prescribers must be trained, successfully complete a knowledge assessment, and enroll to be certified in the Addyi REMS program. Does it work? No difference in reported sexual desire more satisfactory sexual events per month Side-effects: hypotension, fatigue and somnolence Contraindications: Alcohol, liver disease, P450 inhibitors JAMA Intern Med Feb 29

51 Bioidentical Hormones or Compounded Hormones No scientific or medical evidence supports the use of non- FDA bioidentical hormones NOT subject to FDA oversight Inconsistent dose and purity Salivary hormone levels do not correlate with plasma levels

52 DHEAS for Peri- or Postmenopausal Women Does not improve quality of life Associated with increased acne 15% vs 3% Slightly improves sexual function compared to placebo DHEA was not superior to HT for sexual function Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD

53 Use of SERMS for Treatment Tamoxifen for prevention and treatment of breast cancer Raloxifene (Evista) for prevention and treatment of osteoporosis and invasive breast cancer Ospemifene for dyspareunia Bazedoxifene with CEE to prevent breast or endometrial stimulation J Steroid Biochem Mol Biol Dec 25

54 Summary for HRT Use Individualize therapy based on patient s unique benefit and risk profile Safe in healthy, perimenopausal women (50-60 years) Hormones should be prescribed at the lowest effective doses and shortest duration Do not use for the prevention of chronic disease Reevaluate annually

55 Thank you!