Menopausal Management: What Has Changed?

Menopausal Management: What Has Changed? Julia V. Johnson, M.D. Professor and Chair, OB/GYN University of Massachusetts Medical School UMass Memorial Medical Center

Conflicts of Interest None

Learning Objectives Participants will identify changes in clinical research and the impact patient and provider knowledge of menopause symptoms and treatment At the conclusion, the learners will better understand and consider the risks and benefits related to hormone use after menopause

What Happens with the Loss of Ovarian Hormones? Progesterone Irregular menses in perimenopause* Prevent endometrial cancer with hormone therapy No effect on vasomotor symptoms/atrophy or long term health issues Estrogen Vasomotor symptoms (85% of women)* Cardiovascular changes* Decrease in breast tissue* Cardiovascular changes* Decrease in breast tissue* Vaginal/vulvar/bladder changes (40-50% of women)* Bone loss

Menopausal Definitions Perimenopause Perimenopause is defined by the physiologic onset of irregular menses; the period of time between regular menses (premenopause) and final menses Age of onset is 39 51; average age is 46 May be defined by cycle length: Early menstrual cycles < 25 or > 40; 7 days difference from typical cycle Mid/Late menstrual cycles > 60 days The symptoms vary in duration and intensity Vasomotor symptoms last an average of 7 years from onset

The STRAW+10 staging system

When to Treat Perimenopause Irregular menses No treatment needed if not effecting Quality of Life Consider adding progestin (cyclic or continuously) if bleeding is problematic Vasomotor symptoms No treatment needed if not effecting QOL Consider treatment options if needed

Perimenopausal Treatment Options Irregular menses Progestin Cyclic once monthly or up to every 3 months Stop when no menses Continuously Oral, IUD, implant Check FSH and E2 every 6-12 months Vasomotor symptoms Use continuous or cyclic progestin with hormone therapy dose of estradiol (orally or transdermally) FSH/E2 1-2 wk wo/ E2 OCPs Try low dose; can use continuously FSH/E2 1 2 wk wo/ pill

Estrogen Effect: Immediate and Long Term Immediate Vasomotor symptoms (85% of women) Long Term Cardiovascular changes Decrease in breast tissue Vaginal/vulvar/bladder changes (40-50% of women) Bone loss

Vasomotor Symptoms-Limited Effectiveness Symptom management Avoid triggers stress, heat, alcohol Wear layered clothing Less with relaxation techniques exercise, yoga, meditation, breathing Placebo gives 40% reduction, so be cautious of any therapy with minimal effect Herbal management Black Cohosh 20 mg bid (minimal effect by manufacturer) No effect with herbs (dong quai, chaste berry) Phytoestrogens Soy products (minimal effect) Flax seed oil Red clover

Vasomotor symptoms - Moderate effectiveness SSRIs 60% improvement Brisdelle (7.5 mg paroxetine) Decrease of hot flushes by 5/day for placebo vs 5.9/day for paroxetine Lower dose than typically prescribed as Paxil antidepressant (10 mg) Effective with low doses of most SSRI and SNRI Expect some side effects, including decreased libido Gabapentin 50-60% effectiveness Most effective dose is 900 mg qhs or 300 tid Fatigue is common Clonidine Catapress patch

Vasomotor Symptoms Highest Effectiveness Most effective treatment is low dose of estrogen and progesterone Primary form is estradiol Available as oral (daily), transdermal patch(once or twice weekly), transdermal gel (daily), vaginal ring (every 3 months) Alternative is conjugated estrogen Premarin and Duavee Primary form is progesterone Micronized oral or vaginal daily 12 days/month or continuously Alternative is synthetic progestin Norethindrone acetate (combined with oral estradiol) Levonorgesterol (available in patch or as IUD) Medroxyprogesterone acetate (combined with oral CCE)

What if the Best Treatment is Hormone Therapy? Vasomotor symptoms can be debilitating for 15% of women and significantly effect on QOL for 85% Then ask yourself the following questions: Why did so women start hormones in the past? What is the true risk of using estrogen and progestin and estrogen alone? How do we advise women about these risks?

Estrogen Use after Menopause: What Did Science Tell Us? It depends on the point in time considered 1960s: estrogen first recognized and available for menopause symptoms; used for vasomotor symptoms 1970s: recognition of endometrial cancer risk; changed to estrogen + progestin (HT) use 1980s: benefits of HT increased to include prevention/treatment of osteoporosis 1990s: potential benefits for prevention of cardiovascular disease 2000s: Women s Health Initiative changed the outlook for all; designed to demonstrate CV benefit

WHI Study: Estrogen Plus Progestin Arm Design Primary Outcomes Secondary Outcomes Randomized, blinded, placebo-controlled trial 16,608 women aged 50-79 years, average 62 0.625 mg CEE + 2.5 mg MPA vs placebo Coronary heart disease (fatal or nonfatal MI) Invasive breast cancer Stroke, pulmonary embolism, colorectal cancer, hip fracture, and death from other causes Global Index Earliest occurrence of CVD, breast, endometrial, or colorectal CA, stroke, PE, hip fracture, or death due to other causes.

WHI HT Risk Onset Event Yr 1 Yr 2 Yr 5 CVD 1.78 VTE 3.6 Stroke 1.72 Breast CA 1.26

WHI Results: Absolute Risk per 10,000 Women/ Years of HT Use Health Event Excess Cases Attributable to HT Heart attack 7 Stroke 8 Pulmonary embolism 8 Invasive breast cancer 8 Fewer Cases Attributable to HT Colorectal cancer 6 Hip fracture 5

Understanding the WHI Risk with Hormone Therapy (CEE + MPA) Increased risk does not start until after average age of menopause (age =62) Use for more that 5 years increases risk of breast cancer by 8/10,000/year or.1% or 1/1200 risk And risks are NOT the same for estrogen alone

WHI: The Role of Progestin The effects of progestin may be important for breast cancer and atherosclerotic diseases, including CHD and stroke JAMA 2002; 288(3) -Writing Group for the Women s Health Initiative Investigators

Kaplan-Meier Estimates of Cumulative Hazards for Selected Clinical Outcomes Copyright restrictions may apply. The Women's Health Initiative Steering Committee, JAMA 2004;291:1701-1712.

Estrogen Alone Compared to Estrogen + Progestin trial Estrogen alone = estrogen + progestin Both decrease the risks of osteoporotic fractures Both increase the risk of stroke (after age 60+) Estrogen alone estrogen + progestin No increase in the risk of breast cancer No increase in the risk of in myocardial infarction or PE No decrease in the risk of colon cancer

So What Do We Tell Patients? Vasomotor symptoms are temporary and will improve slowly over time There is not increased risk immediately (more soon!) and we have time to lower the dose for symptoms improve Follow them closely and decrease every year until able to stop She will say: BUT WHAT ABOUT MY HEART AND BREAST?

Cardiovascular Disease: Negative and Positive Effects Risk may be increased with long term use --Appears to impact some risks of vascular disease after age 60 or 70 --May be related to progestin, not estrogen Benefits show a decrease immediately after menopause -- CV mortality is decreased with HT use for the 50-59 age group < 10 years from menopause --There is no increase in MI risk for women aged 50-59 or 60-69 (or < 20 years from menopause --Less risk with E2 alone

Other Research Cardiovascular Benefits Observational studies and primate models show decreased risk of CHD with early HT use Early and continued HT shows prevention and decreased progression of atherosclerosis Meta-analysis of 23 randomized HT vs. placebo trials (> 30,000 women) showed decreased risk of CHD in women < age 60 or < 10 years after menopause (ER = 0.68, CI = 0.48 0.96) Cardiac angiography study demonstrated decreased risk of atherosclerosis with HT use These lead the Endocrine Society to state that HT benefits outweigh risk of CHD for women with 10 years of menopause

Most Recent Study: Kronos Early Estrogen Prevention Study (KEEP Trial) 750 women over 8 years from 8 sites Three groups: 0.5 mg estradiol patch + cyclic 200 mg micronized progesterone OR 0.45 mg oral CEE + cyclic MP OR placebo Women aged 42 58 within three years of last menses Primary outcome are intermediate markers for CHD-- carotid intimal medial thickness and accrual of coronary calcium No increase in MI, stroke, breast cancer to date Stable coronary vascular medial thickness

What to Do to Potentially Lower Risk of Hormone Therapy Consider non-oral forms of estrogen Lower risk of thrombotic event with transdermal (or vaginal) estradiol Consider alternative progestin Micronized progesterone Norethindrone acetate or levonorgestrel Reduce gradually to lessen return of hot flushes

Cardiovascular benefit HT at the age of typical menopause All studies DO suggest a short term benefit of HT use WHI is the ONLY study following women into their 70s and the risk of stroke increases in the 60s and MI in the 70s The long term CV benefit has not yet been proven; we may never know what it is!

WHI: What Happened 18 Years After Stopping the Study So how do you tell your patients that stopping may be beneficial for their long term health? JAMA 2017; 318(10):927-38. No long term increase in either all-cause or cause-specific mortality amongst women who received hormone therapy for up to 5.6 years with combined HT or 7.2 years with estrogen alone And talk about breast cancer risk

Breast Cancer Risk WHI Small but Significant after 5 Years WHI did not specify the type of breast cancer: still ER and/or PR positive cancer most concerning The severity of breast cancer is just as variable; however no increase in rate of mortality No difference based positive family history The difference of E + P and E alone risk does suggest that different progestins are important

Other Limited Studies on Breast Cancer There is a significant decrease in breast density after stopping HT; may improve imaging for dense breast tissue be sure your patients do mammogram yearly on hormone therapy Previous studies (Nurses Health Study and Million Women Study) did show an lower, but significant, increase in breast CA of 1.42 and 1.48 Only new long term study, the KEEP trial, shows a negative impact at 8 years BUT YOUR PATIENT STILL HAS DYSPARUENIA?

Vaginal/Vulvar Changes Vaginal and vulvar thinning are a normal change without ovarian estrogen; loss of collagen, adipose, and thinning of the epithelium and subcutaneous tissue Decreased production of mucus from vaginal glands and increase in ph. Can lead to dyspareunia, postcoital bleeding, severe dryness, and vaginitis The appearance of the vagina and vulva change to become paler, thinner, and less rugae Significant symptoms affect 40-50% of women

Vaginal Atrophy/Dysparuenia If mild, lubricants with intercourse: any vegetable or coconut oil and/or use Replens, Astroglide twice weekly If moderate, Ospemifene (Osphena) is a SERM approved for vaginal atrophy Significant side effect is hot flushes and muscle cramps Has thrombotic risk of estradiol given orally If moderate or severe, most effective therapy is vaginal estrogen alone (no progestin) Cannot measure increase in serum estradiol with vaginal use

Vaginal Estrogen Utilization Estradiol is the only treatment that improves vaginal thickness and lubrication May need dilators if vaginal constriction is an issue Theoretically no impact on breast tissue or cardiovascular system Can consider long term use for a long term symptom Mode of delivery CEE or estradiol cream (daily for 1-2 wk; then 2 x/wk) Estradiol ring (every 3 months) Estradiol tablet (daily for 1-2 wk; then 2 x/wk)

Study of Vaginal E2 or Lubricant vs Placebo: JAMA Internal Med 2018 Compared estradiol tablet for 12 weeks vs OTC lubricant vs placebos Found no difference in symptom relief compared to placebo Suggests that tablets alone may not be sufficient and any material works as a lubricant Solution: If pain continues, try cream externally or change from vaginal tablet to cream or ring

Patients Can Use HT Long Term Often start vaginal/vulvar estradiol when on lower systemic level of hormone therapy Can use the combination that works for your patient often cream is best, but can try any form of estradiol Sometimes less cost and hassle from compounding pharmacies Can continue as long as needed safely

Summary: what your patients need to understand Menopause is a physiologic event with wide variation in age, duration of change, and symptoms Hormonal changes CAN be managed during perimenopause and with menopausal symptoms Risks of estrogen use is modest, but important to know: Estrogen and progestin used together increase the risk of breast cancer by 1/1200/yr every year of use after 5 years Estrogen appears to increase the risk of stroke after age 60 and MI after age 70; no risk in the 50s (and possible benefit) Estrogen is the most effective, but not only treatment, for vasomotor symptoms; likely can reduce dose/stop in the 60s Estrogen vaginally is very effective for vaginal atrophy and is not significantly absorbed in the bloodstream; continue long term

FDA guidelines for hormone use Use all medications, including hormones, at the lower effective dose for the shortest time needed BUT YOU CAN CONSIDER HORMONE THERAPY TO RELIEVE SYMPTOMS THAT SIGNIFICANTLY EFFECT QUALITY OF LIFE

THANK YOU FOR YOUR ATTENTION Questions??