Management of Menopausal Symptoms Tammie Koehler DO, FACOG 1 Menopause Permanent cessation of menstruation that occurs after the loss of ovarian activity Determined to have occurred after 1 full year of no menstrual cycles Median age in US is 51 years 2 1
Menopausal transition (perimenopause in past) Fluctuations in hormone levels due to ovarian function slow down Serum levels of estradiol, progesterone decrease, FSH increases Results in physiological changes and clinical symptoms Most common are vasomotor and vaginal symptoms 3 Vasomotor symptoms Sudden sensation of extreme heat in upper body especially face, neck and chest. Last typically 1-5 minutes Associated with perspiration, flushing, chills, clamminess, anxiety and occasionally palpitations May interfere with sleep and cause chronic sleep disruption Episodes vary in frequency and duration 87% of women experience these on daily basis, and approximately 33% experience more than 10 episodes a day May persist longer than previous estimate of 1 year after cessation of periods, published reports indicate overall duration remains unclear. Median durations of 4-10.2 years 4 2
Pathophysiology of Hot Flashes Not fully understood but related to multiple factors Changes in reproductive hormones, decrease in estrogen and increase in FSH, play a critical role however they are not solely responsible as symptoms vary greatly among women in the menopausal transition Thermoregulatory zone narrows and becomes more sensitive to subtle changes in body temperature Estrogen widens this zone Serotonergic, noradrenergic, opioid, adrenal and autonomic systems also play a role 5 Risk Factors for Vasomotor symptoms Racial and ethnic differences have been shown in observational studies The Study of Women s Health Across the Nation assessed 14,906 women age 40-55 with diverse ethnic backgrounds African Americans reported most symptoms Asian women the fewest Making consideration of diet of high soy may account for the differences Differing cross-cultural perceptions and reporting 6 3
Vaginal Symptoms Atrophy-direct consequence of the hypoestrogenic state Results in anatomic and physiologic changes in the genitoutinary tract Loss of superficial epithelial cells causing thinning of tissue Loss of vaginal rugae Loss of elasticity with narrowing and shortening of the vagina Vaginal ph becomes more alkaline, alters the normal flora resulting in increased risk of urogenital infections. Vaginal secretions decrease Loss of subcutaneous fat in labia majora Narrowing of the introitus, fusions of the labia minora and shrinking of clitoral prepuce and urethra 7 Hormonal Treatment Most effective estrogen or combination HRT (at standard doses) shows 75% reduction in weekly hot flush frequency and severity according to Cochran meta-analysis of 24 randomized controlled trials that included 3,329 participants. There is no Data to support progestin only, testosterone or compounded bioidentical hormones Goal of treatment is the lowest effective dose for the shortest period of time to control symptoms 8 4
Risks Risk-benefit ratio must be considered and the treatment individualized with a end goal Thromboembolic disease and breast cancer WHI study reported slightly increased risk of breast cancer, coronary heart disease, stroke and venous thromboembolic events but a decrease in risk of fracture and colon cancer after an average of 5 years treatment. In estrogen only arm there was an increased risk of thromboembolic events but not an increased risk of cardiovascular events or breast cancer WHI was aimed at assessing HRT for primary coronary heart disease prevention in women aged 50-77. Most past the menopausal transition. 9 Testosterone in combination with HRT Cochran meta-analysis of 35 trials with 4,768 participants shows no significant benefit and potential adverse effects: Lipid parameters Clitoromegaly Hirsutism Acne The same study suggests that the addition improved sexual function scores in postmenopausal women 10 5
Bioidentical Hormones Plant-derived and chemically similar or structurally identical to those produced in the body Micronized progesterone and estradiol (regulated by FDA) Compounded preparations No rigorous clinical testing for safety or efficacy. Concern for potency, purity, and quality. Consideration for under or over dosage due to variable bioavailability and bioactivity 11 Non-Hormonal Medications Selective serotonin reuptake inhibitors (SSRI) and selective serotonin-norepinephrin reuptake inhibitors (SSNRI). Randomized controlled trial of 365 women found a 62% reduction vs 41% placebo for moderate to severe hot flashes with treatment effect maintained for 1year Meta-analysis demonstrated significant reduction compared to placebo. Paroxetine(7.5mg/d) is the only non-hormonal therapy approved by the FDA for treatment of vasomotor symptoms. Adverse effects included nausea, dizziness, dry mouth, nervousness, constipation, somnolence, sweating and sexual dysfunction. These generally resolved with time or dose adjustment. 12 6
Clonidine Centrally acting alpha 2-agonist. (not FDA approved for this indication) Systematic review and meta-analysis reported a small benefit with clonidine 0.1mg/d compared to placebo Adverse effects were dry mouth, insomnia and drowsiness, at this dose blood pressure was not adversely affected 13 Gabapentin A gamma amniobutyric acid analog Not FDA approved for this indication Randomized control trial of gabapentin 900mg/d demonstrated a 45% reduction in frequency and a 54% reduction in severity. Adverse effects include dizziness, somnolence and peripheral edema. 14 7
Phytoestrogens Plant derived substances with estrogenic biologic activity Isoflavones, genistein and daidzein, found in soy porducts and red clover. Original interest stemmed from observation that the Asian women experience fewer vasomotor symptoms and their diets are rich in soy based products. Studies are limited by small sample size. A Cochran metaanalysis or 30 placebo controlled trials of high levels of phytoestrogens for treatment of vasomotor symptoms and found no significant difference from placebo 15 Herbal remedies Chinese herbal medicine, Black cohosh, Ginseng, St. John s wort and Ginkgo. Dong Quai, limited data to support safety and effectiveness, one small RCT shows no difference from placebo. Adverse effects: photosensitivity and increased risk bleeding in patients on warfarin One study Chinese herbal medicine plus acupuncture was found to be as effective as HT in relieving symptoms Black Cohosh- data is conflicting regarding efficacy and safety due to limited study quality. Reports of liver toxicity have been made. Studies have not shown that herbs as listed either alone or in combination are superior to placebo. Vitamins- limited data on the effectiveness of vitamins for treatment. One study shows marginal reduction, (one less hot flush/day) with vitamin E 800IU/d 16 8
Alternative Techniques Acupuncture- meta-analysis of 6 studies showed no benefit over placebo Reflexology- no significant reduction in symptoms compared to non-specific foot massage Preliminary data suggest the local injection of anesthetic into the stellate ganglion may reduce vasomotor symptoms in women with contraindications to HRT. 17 Management of vaginal symptoms Estrogen therapy All low dose systemic estrogen formulations are FDA-approved. Oral conjugated estrogen as low as 0.3mg/d and transdermal estradiol of 12.5mcg/d have demonstrated improvement Local vaginal estradiol or conjugated equine estrogen in the form of cream, ring and tablet are effective in treatment. Typical dosage is daily for 1-2 weeks as induction therapy and then low dose 2-3 times weekly for maintenance dosage. Systemic absorption of vaginal estrogen has been documented using a daily low-dose preparation with 25mcg. Cochran meta-analysis of 19 trials with 4,162 women found no association with increased risk of endometrial hyperplasia compared to placebo. 18 9
Estrogen Agonists and Antagonists Synthetic compounds that selectively stimulate or inhibit the estrogen receptors of different target tissues. Raloxifene and tamoxifen are not effective for the treatment of menopausal vaginal symptoms. Ospemifene is a novel estrogen agonist/antoagonist that improves vaginal atrophy without stimulating the endometrium. A study of 826 postmenopausal women randomized to 30 mg/d vs 60 mg/d. Showed that 60mg/d was effective for improving vulvovaginal atrophy. Adverse effects: hot flushes, vaginal discharge, muscle spasms, genital discharge and excessive sweating 19 Non-hormonal therapies Vaginal lubricants- water or silicone based, are intended to be used to relieve friction and dyspareunia secondary to vaginal dryness during intercourse. Vaginal moisturizers are intended to trap moisture and provide long term relief of vaginal dryness Prospective studies have demonstrated that moisturizers improve vaginal dryness, ph balance and elasticity and reduce vaginal itching, irritation and dyspareunia. 20 10
What about breast cancer patients Non hormonal pharmacologic treatments, lifestyle alterations and alternative or complimentary therapy. SSRI s, SSNRI s show some decrease in severity and frequency of vasomotor symptoms. In a number of RCT s significant reduction in hot flushes among breast cancer survivors using venlafaxine was seen. The optimal balance between effectiveness and adverse effects seems to be 75mg po daily. Other trials have evaluated low doses of paroxetine, fluoxetine and citalopram with reduction of symptoms. Short term use of hormonal methods may be considered in women with severe or refractory symptoms following appropriate counseling with their oncologists and about potential risks. 21 Bibliography ACOG-practice bulletin #141, January 2014 Cochran data base systemic reviews 2004, Issue 4. Postmenopausal estrogen/progesterone Interventions Trial. Obstet Gynecol 1998;92:982-988 Writing Group for the Women s Health Initiative Investigators. JAMA 2002;288:321-323 Women s Health InitiativeSteering Committee. JAMA 2004;291:1701-12 ACOG Committee Opinion Number 532 Climacteric 2009;12:16-25 Obstet Gynecol practice bulletin no 126/ 2012 Questions???? 22 11