MENOPAUSE I have no disclosures WHAT’S NEW? WHAT’S SAFE? Sara Whetstone, MD, MHS OBJECTIVES •To describe risks of HT by age and menopause onset •To recommend specific HT regimen for women who undergo early menopause and who undergo menopause at the expected time BP is a 52yo woman who HT – Hormone therapy cannot sleep due to her hot flashes. Her last period was ET – Estrogen only therapy approximately 8 months EPT – Estrogen-progestin therapy ago. She is miserable. She GLOSSARY is interested in exploring HT CEE – Conjugated equine estrogen but worried specifically about risks of HT. In the MPA – Medroxyprogesterone acetate past, she has had really bad MP – Micronized progesterone experiences with progestin therapy. TREATMENT OF VASOMOTOR SYMPTOMS Vasomotor symptoms Most effective treatment: systemic hormone therapy (HT) with estrogen therapy INDICATIONS Prevention of bone loss If uterus present... If uterus absent… FOR HT (FDA-APPROVED) Hypoestrogenism (caused by hypogonadism, oophorectomy, or POI) Genitourinary syndrome of Estrogen + Progestin Estrogen alone menopause (GSM) (or vulvo-vaginal atrophy) (EPT) (ET) RISKS AND BENEFITS OF HT IN WOMEN AGES 50-59 OR <10 YEARS OF BENEFITS/RISKS MENOPAUSE OF HT AMONG WOMEN 50-59 Manson JE et al. NEJM, 2016 Santen et al. J Clin Endocrinol Metab. 2010 BP is a 52yo woman who CONTRAINDICATIONS TO SYSTEMIC HT cannot sleep due to her hot flashes. Her last period was .Unexplained vaginal bleeding approximately 8 months .Severe active liver disease ago. She is miserable. She is interested in exploring HT .Estrogen-sensitive breast or endometrial cancer but worried specifically .Coronary heart disease about risks of HT. In the .Stroke past, Whatshe has type had of estrogen really therapy bad do you usually start with? .Personal history or inherited high risk of venous 1)experiences Oral CEE with progestin thromboembolism 2)therapy. Micronized oral 17-beta estradiol 3) Transdermal 17-beta estradiol 4) Oral CEE + bazedoxifene SYSTEMIC TISSUE SELECTIVE ESTROGEN COMPLEX (TSEC) HORMONE THERAPY (HT) FDA approved for Estrogen present to treatment of REGIMENS treat vasomotor vasomotor symptoms symptoms and osteoporosis ACOG Bulletin 141: prevention Management of menopausal CEE/BZA symptoms, 2016. (0.45mg/20mg) SERM to block estrogen action in Progestin is NOT endometrium/uterus needed BZA - Bazedoxifene TABLE 1 Target Tissue TSEC Oral HT (ET and EPT) VMS Improved frequency and severity Improved frequency and severity BP was excited about an Bone Improved BMD Improved BMD, decreased fracture risk option for HT that did not Endometrial Neutral with EPT, increased with ET alone Neutral at 2y neoplasia if uterus present involve a progestin. After Breast cancer Neutral at 2y Increased in WHI trial <1/1000 counseling, BP started 2 fold risk with BZA, no additive 2 fold risk with oral ET & EPT, potentially CEE/BZA with good relief VTE risk risk with CEE/BZA less with transdermal therapies of her vasomotor symptoms. TISSUE EFFECTS OF TSEC VS. TRADITIONAL HT Pinkerton JV et al. Clin Obstet Gynecol, 2018. TG is a 64yo woman who underwent menopause at age 49. JOINT PAIN AND HT She has noticed increased joint .Evidence of estrogen binding to estrogen stiffness and prolonged fatigue receptors on joint tissues after exercising in the last 18 .Inconsistent evidence about effects of ET on months. She was encouraged by osteoarthritis and arthralgia .May be benefits of estrogen and SERMs on joint her PCP to present to GYN to pain discuss initiating hormone . In WHI: replacement therapy for her .Women on CEE + MPA (vs placebo, 47.1% vs symptoms. Her medical history is 38.4%) had less joint pain/stiffness, more discomfort when stopping HT notable for hypertension and .Women on CEE had statistically significant less hyperlipidemia. joint pain (vs placebo, 76.3% vs 79.2%) TG is a 64yo woman who underwent menopause at age 49. She has noticed increased joint stiffness and prolonged fatigue after exercising in the last 18 RISKS OF months. She was encouraged by HT BY AGE her PCP to present to GYN to discuss initiating hormone Would you start replacement therapy for her TG on HT? symptoms. Her medical history is 1) Yes notable for hypertension and 2) No hyperlipidemia. 3) Maybe Manson JE, JAMA 2013. Potential risk Age and/or time from menopause onset <60 years or <10 years from >10 years from menopause menopause Coronary heart Potential for increased risk NAMS ALGORITHM Reduced risk of CHD disease of CHD All-cause Significant reduction in all-cause No protective effect of HT mortality mortality Meta-analysis of RCTs: No Meta-analysis of RCTs: Stroke increased risk of stroke Increased risk of stroke Observational studies: mixed Rare risk but significantly VTE Higher absolute risk increased with HT SUMMARY OF HEALTH RISKS OF HT BY AGE AND/OR TIME FROM MENOPAUSE ONSET Manson JE, Menopause, 2015. “For women who initiate HT more than 10 to 20 years from menopause onset or when aged 60 years or older, the benefit-risk ratio appears less favorable than for younger women because of CVD RISK AND greater absolute risks of CHD, TIME SINCE stroke, VTE, and dementia.” MENOPAUSE ONSET 2017 HT Position Statement of NAMS PB is 66yo G0 woman who underwent bilateral CONSEQUENCES OF EARLY MENOPAUSE AND oophorectomy at age 40 after PRIMARY OVARIAN INSUFFICIENCY her sister was diagnosed with ovarian cancer. She was started on HRT for very bothersome hot flashes. She Vasomotor Bone loss and Increased heart symptoms GSM osteoporosis disease presents to discuss continuation of HRT. She is currently taking PO conjugated equine estrogen Dementia and Depression and Higher overall (CEE) and continuous cognitive anxiety related decline disorders mortality medroxyprogesterone acetate (MPA). Vasomotor symptoms MANAGEMENT OF EARLY MENOPAUSE Hormone replacement INDICATIONS Prevention of bone loss Estrogen therapy Exercise • Dosage higher than usual FOR HT post-menopausal ET (FDA-APPROVED) Healthy diet Hypoestrogenism • Monitoring estradiol levels (caused by hypogonadism, oophorectomy, or POI) Adequate calcium and NOT recommended vitamin D intake Progestin necessary if patient Genitourinary syndrome of Avoidance of smoking has intact uterus menopause (GSM) (or vulvo-vaginal atrophy) PB is 66yo G0 woman who underwent bilateral oophorectomy at age 40 after her sister was diagnosed with ovarian cancer. She was started on HRT for very bothersome hot flashes. She presents to discuss continuation of HRT. She is currently taking PO conjugated equine estrogen (CEE) and continuous medroxyprogesterone acetate RECOMMENDED TREATMENTS ACOG Committee Opinion, 2017. (MPA). COMMON HT Estrogen replacement (E+P) REGIMENS • Transdermal recommended (over oral) • Can also use vaginal ET • Lower risk of VTE • Rovinski D (2018): Oral HT was CHOOSING associated with increased risk of WHICH REGIMEN VTE, while non-oral HT was not • Lower risk of stroke TO PRESCRIBE • Lower risk of hypertriglyceridemia Bottom Line: Start with transdermal estrogen patch (17-beta estradiol) BREAST & CV EFFECTS OF PROGESTINS Progestin therapy Recommendation for oral micronized progesterone (MP) CHOOSING Sequential: 200mg/day x 12 WHICH REGIMEN days per month Continuous: 100mg daily TO PRESCRIBE Llaneza P, Gynecol Endocrinol, 2018. Disadvantages Using LNG-IUS for endometrial (1) Higher dose of E+P protection would be considered an off- therapy label use (2) ?inferior to higher dose HT in regards to BMD Reasonable to consider in women who do not tolerate oral progestins WHAT ABOUT WHAT ABOUT LEVONORGESTEREL Can be utilized by women who desire IUD? ET at non-contraceptive levels and who OCPS? are still at risk of pregnancy Advantages Effective for endometrial protection for peri-menopausal and post-menopausal (1) Easier to use, less stigma women using ET (2) Offers contraception PB is 66yo G0 woman who Should PB stop HT? underwent bilateral 1) Yes WHEN TO STOP HORMONE REPLACEMENT? oophorectomy at age 40 after 2) No her sister was diagnosed with ovarian cancer. She was 3) It depends… .Treatment for women with primary ovarian insufficiency/early started on HRT for very menopause should continue until the average age of natural bothersome hot flashes. She menopause (50–51 years) presents to discuss continuation .Treatment may continue past age 50–51 years if a woman has of HRT. She is currently taking clinical symptoms or indications. PO conjugated equine estrogen .Regardless of age, the decision to continue HT should be (CEE) and continuous individualized and based on a woman’s symptoms and the risk– medroxyprogesterone acetate benefit ratio. (MPA). WHEN TO STOP? Extended use may benefit women for relief of VMS, prevention of bone loss and fracture, and treatment/prevention of GSM DURATION OF Vasomotor symptoms recur in 50% of women Many of the benefits/risks of HT do not persist beyond 5 to 7 years TREATMENT Elevated (but rare absolute risk) of breast cancer with CEE + MPA in median 13 yr follow-up CVD risk became neural Bone protection rapidly dissipates after HT discontinuation Significant reduction in breast cancer with CEE during 13 year follow-up All-cause mortality was neutral in CEE + MPA group in 13 year follow-up Data lacking on benefits/risks of longer duration and with discontinuation of HT OUR ADVICE FOR PB: KG is 64yo P2 woman with no significant PMH who presents .Recommend discontinuation of HT for her routine gynecologic visit. She reports dyspareunia .If PB is hesitant to stop HT or has recurrent bothersome menopausal despite lubrication. She symptoms, would recommend declines vaginal estrogen, .Trying non-hormonal treatments .Switching to transdermal estrogen stating “she doesn’t want to try .Switching to micronized any hormonal medications as progesterone she doesn’t perceive them as .Lowering dose as tolerated safe.” .Reassessing HT on an annual basis GENITOURINARY SYMPTOMS AND SYNDROME OF Vulvovaginal MENOPAUSE SIGNS OF GSM atrophy …a collection of signs and symptoms associated with a decrease in estrogen and other sex steroid hormones involving changes to the labia majora/minora, Atrophic vaginitis clitoris, vestibule/introitus, vagina, urethra, and bladder.