Menopause Lecture Notes Fall 2024 PDF

Menopause SHERYL MATHE W, PHARMD, BCPS PHAR508, FALL 2024 S L I D ES A D A P T E D F R O M L O U I S E PA R E N T - S T E V E N S , P H A R M D , B C P S Goals and Objectives Identify the symptoms of menopause Identify the risks versus benefits of hormone therapy for menopause List the non-ho...

Menopause SHERYL MATHE W, PHARMD, BCPS PHAR508, FALL 2024 S L I D ES A D A P T E D F R O M L O U I S E PA R E N T - S T E V E N S , P H A R M D , B C P S Goals and Objectives Identify the symptoms of menopause Identify the risks versus benefits of hormone therapy for menopause List the non-hormonal options for the management of menopausal symptoms Develop a patient-specific treatment plan for the management of menopausal symptoms Required Reading Pharmacotherapy (DiPiro) 12th ed Chapter 102: Post Menopausal Hormone Therapy Additional materials posted on Blackboard Table 1: Risks and Benefits of HT Table 2: Agents used for postmenopausal HT Table 3: Example ET/EPT regimens and expected vaginal bleeding patterns What is Menopause? A natural life event → not a disease Permanent cessation of menses, following the loss of ovarian follicular function Decreased production of sex hormones (estrogen, progestin) Stages of natural menopause: Perimenopause Menopause (amenorrhea >12 months) Postmenopause (1 year after menopause and beyond) Induced menopause → due to removal of ovaries or ablation of ovarian function Epidemiology Median age of onset in the US = 51 years (can vary from 40-58 years) Onset before age 40 = premature ovarian insufficiency (POI) Women are spending nearly 40% of their lives in post-menopause ~6,000 women in the US reach menopause everyday Clinical Presentation Vasomotor symptoms AKA hot flashes, night sweats (diurnal pattern) Develop in up to 80% of women and last ~7.5 years on average Wane with time since menopause Sudden feeling of warmth and increased sweating/flushing Severity, duration, and frequency vary from woman to woman 25% of women experience severe vasomotor symptoms Clinical Presentation Genitourinary Syndrome of Menopause (GSM) Vaginal atrophy Thinning, drying, and inflammation of vaginal walls Dyspareunia (painful intercourse) Urinary symptoms Urinary urgency, dysuria Recurrent UTI Clinical Presentation Psychological symptoms Increased risk of depression Mood changes Poor concentration and memory (reach premenopausal levels again after menopause) Decreased libido Insomnia and fatigue (due to nocturnal hot flashes) Breast atrophy Due to decrease in estrogen Clinical Presentation Increased risk of osteoporosis Estrogen is essential for bone growth Major cause of morbidity in post-menopausal women Increased risk of CV disease? #1 cause of death in post-menopausal women Menopause associated with more adverse lipid profile Diagnosis No menses for one year In absence of other causes for amenorrhea Diagnosis typically retrospective Elevated FSH levels (> 40) Management Goals of therapy: Relieve symptoms Improve quality of life Minimize adverse effects Treatment should be individualized Important Terms: HT = hormone therapy MHT = menopausal hormone therapy ET = estrogen therapy EPT = estrogen progesterone therapy Guidelines Numerous guidelines available ◦ NAMS: 2023 Nonhormone Therapy Position Statement https://menopause.org/wp-content/uploads/professional/2023-nonhormone-therapy-position- statement.pdf ◦ NAMS: 2022 Hormone Therapy Position Statement https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy-position- statement.pdf ◦ AACE: The 2017 Menopause Position Statement Updated https://journals.aace.com/doi/pdf/10.4158/EP171828.PS ◦ NAMS: 2020 Genitourinary Syndrome of Menopause Position Statement https://journals.lww.com/menopausejournal/Fulltext/2020/09000/The_2020_genitourinary_syndrome _of_menopause.5.aspx Non-Pharmacologic Management Hot flash trigger avoidance Wear layered clothing Lower room temperature Decrease intake of spicy foods, caffeine, hot beverages Regular exercise Aerobic (CV protection) and weight-bearing (bone protection) Diet Heart-healthy Adequate calcium and Vitamin D Pharmacotherapy Hormone therapy Estrogen +/- progestin Tissue selective estrogen complex (TSEC) SERMs Non-hormonal therapy Serotonergic agents (SSRI/SNRI) NK3R antagonist Antiepileptic drugs Antihypertensives Local (vaginal) therapies Hormone Therapy  HORMONE THERAPY (HT) ESTROGEN ONLY (ET) ESTROGEN + PROGESTERONE (EPT) Systemic Estrogen Localized Estrogen (oral, transdermal, (oral, transdermal, (low-dose vaginal) high-dose vaginal) high-dose vaginal) ESTROGEN + BAZEDOXEFINE (oral) Estrogen Therapy (ET) Systemic estrogen monotherapy FDA-approved indications: Vasomotor symptoms Genitourinary symptoms (GSM) Premature hypoestrogenism Prevention of bone loss For use in women without a uterus Increases risk of endometrial cancer if used in women with a uterus Estrogen-Progestin Therapy (EPT) Systemic estrogen-progestin therapy For use in women with intact uterus Uterine protection is the only reason to add progestin component to ET Estrogen + Bazedoxifene (Duavee) Systemic (oral) estrogen + SERM = TSEC (tissue-selective estrogen complex) Bazedoxefine = estrogenic in bone, antiestrogenic in uterus/breast Indication (in women with uterus): Moderate-severe vasomotor symptoms Prevention of postmenopausal osteoporosis Advantage: do not need to add a progestin component Same risks/contraindications as ET Localized Estrogen Therapy (ET) Vaginally administered low-dose estrogen that does not result in clinically significant systemic absorption Indication: menopausal vaginal atrophy Does NOT require concomitant progestin therapy (even if a woman has a uterus) Therapeutic response typically after 2 weeks of daily use Maintenance dosing typically 2-3x weekly Risks versus Benefits of Hormone Therapy Women’s Health Initiative (WHI) Randomized, double-blind, placebo-controlled trial (1991) To evaluate effects of MHT on heart disease, osteoporosis, cancer in women aged 50-79 years (mean age 63.5 years) Two arms: Estrogen + progestin (in women with an intact uterus) – n=16,608 Estrogen alone (in women with history of hysterectomy) – n=10,739 Primary outcome: incidence of coronary heart disease (CHD) Primary safety outcome: invasive breast cancer Other outcomes studied included: stroke, PE, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes WHI Results Estrogen + progestin arm terminated early (5.6 years) due to increased breast cancer risk and unfavorable risk-benefit ratio Estrogen only arm terminated early (7.2 years) due to increased stroke incidence Key takeaways: Dramatic reduction in MHT prescriptions after results were published in 2002 Only studied one dose and formulation Important to note that it was an older population (average age 63 years), on average ~12 years past menopause Subsequent subanalyses of the WHI and other studies have shown that younger women/closer to menopause had a more beneficial risk-benefit ratio Importance of Timing Critical window hypothesis = effects of HT depend on the timing of initiation with respect to age and/or onset of menopause, with benefits limited to early initiation Early use: < 10 years since menopause and < 60 years old at initiation No change or decreased risk of CHD Late use > 10 years since menopause and > 60 years old at initiation Increased risk of CHD, stroke, and VTE Overall, HT should not be used for chronic disease prevention, but is a reasonable option for managing menopausal symptoms Established Benefits Vasomotor symptoms Osteoporosis Reduced risk of hip, spine, and wrist fractures Protective effect does not persist after cessation of treatment Vaginal atrophy Established Risks Thromboembolic disease Breast cancer Cardiovascular disease Endometrial cancer Ischemic stroke Gallbladder disease Hypertriglyceridemia Absolute Contraindications for HT Venous Undiagnosed Severe active liver thromboembolism vaginal bleeding disease (VTE) High risk of History of CHD or thromboembolic History of stroke MI disease Personal history of breast, endometrial, or ovarian cancer Absolute Contraindications In women with absolute contraindications to systemic estrogen, localized low- dose vaginal estrogen may be acceptable Relative Contraindications Use cautiously, monitor closely! Endometriosis or uterine fibroids Gallbladder disease or moderate liver disease Hypertriglyceridemia Migraines Uncontrolled DM or HTN Obesity Age >60 years or >10 years since menopause (at initiation) Strong family history of breast or ovarian cancer Current tobacco use Product Selection and Dosing for HT Product Selection Start with the lowest effective dose for symptom control Fewer adverse effects and better overall benefit-risk profile Various routes available (oral, transdermal, topical, intravaginal, intramuscular) Use transdermal route in patients with: Increased risk of VTE Gallbladder disease HTN Hypertriglyceridemia Product Selection Patients with a uterus must use combination EPT (for systemic HT) Can use separate estrogen and progestin products, or combination products Preferred progestin is micronized progesterone EPT Dosing Regimens Variety of dosing regimens available Continuous cyclic EPT – estrogen administered daily, progestin coadministered 12-14 days of 28 day cycle Scheduled withdrawal bleeding in ~90% of women Continuous combined EPT (preferred) – can use oral or transdermal preparations, or administer systemic estrogen + levonorgestrel IUD Absence of withdrawal bleeding (after 1 year for majority of patients) Patients should be counseled about potential for bleeding Patient should be involved in selection of regimen Resumption of bleeding does not indicate return of fertility Adverse Effects of Systemic HT Nausea Breast tenderness Headaches *Side effects often diminish with Increased BP continued use Leg cramps *If persistent, try dose adjustment Mood swings or change in product Decreased libido Skin irritation (with transdermal products) Localized Low-Dose Vaginal ET ◦Indicated for vaginal atrophy ◦Limited systemic absorption occurs—may be okay to use in women with absolute CI ◦No proven systemic benefits ◦Does not require concurrent progestin use ◦Products ◦ Low dose vaginal ring (7.5mcg/day of estradiol) ◦ Cream/Tablets (conjugated estrogens, estradiol estropipate) Place in Therapy for ET/EPT Post-menopausal women with vasomotor symptoms Safety profile most favorable in healthy women