What s New in Menopause Management Leslee L. Subak, MD Professor of Obstetrics, Gynecology & Reproductive Science University of California, San Francisco Objectives Define the menopause transition Review menopausal symptoms Evidence-based treatments for vasomotor and vaginal symptoms How to use and stop using hormone therapy
Stages of Reproductive Aging Age: young ~45-50 yo ~ >50 yo Stage: Reproductive Menopause Transition Postmenopause regular cycles irregular/missed cycles no menses >12 mo regular ovulation intermittent anovulation anovulation fertile less fertile infertile E 2 50-200pg/ml same or maybe higher 0-15 pg/ml T 400 pg/ml same same FSH 10 miu/ml same or higher >100 miu/ml LH 10 miu/ml same or higher >100 miu/ml Soules, NIH Consensus Conference, Fertil Steril, 2001 Definitions Perimenopause - several years before and 1 year after menopause Early menopause transition Late menopause transition Menopause cessation of menstruation End of ovulation and cyclic bleeding End of fertility and need for birth control Positive experience for many women Marker of aging
What Happens at Menopause? Cessation of menses end cyclic bleeding end of ovulation and fertility marked (retrospectively ) by final menstrual period Changes in hormones estrogen, progesterone, FSH, LH, GnRh Positive experience for many women Aging What Symptoms are Related to Menopause? Many reported by middle-aged women Few associated with menopause transition Hot flushes and night sweats Vaginal dryness that can cause dyspareunia Trouble sleeping Depressive symptoms Other common symptoms may be related to aging, stress, other symptoms Nelson, Evidence Report #120, 2005
Problems Peri-Postmenopause Abnormal uterine bleeding Vasomotor symptoms Genital atrophy Decrease in skin collagen Rapid bone loss Increase in coronary heart disease Increase in Alzheimer s disease
Prevalence and Risks Factors for Hot Flushes % of women Hot Flushes* Risk Factors Surgical menopause African-American, Latina Higher BMI Cigarette smoking *Gold, Am J Epidemiol, 2000 Randolph, J Clin Endocrinol Metab, 2004 Etiology of Hot Flushes Thermoregulation in Women without Hot Flushes Thermoregulation controlled by anterior hypothalamus and local vascular factors Core body temperature (CBT) above threshold results in vasodilation, sweating and heat release Thermoregulatory null zone CBT below threshold results in vasoconstriction, shivering and heat conservation and production Thermoregulation in Women with Hot Flushes Altered thermoregulation CBT at which women with hot flushes vasodilate and sweat is 0.3 degrees C lower Narrowed thermoregulatory null zone than premenopausal women or women without flushes.
Etiology of Hot Flushes Hot flush is a heat release mechanism But occurs at normal core body temp Not simply estrogen deficiency E 2 in women with and without flushes similar other women with low, high or variable estrogen levels do not flush Abnormality of hypothalamus related to CNS adrenergic or serotonergic neurotransmission? CNS opioids peripheral vascular instability Evaluation of Hot Flushes History crucial Age (mean age 52; 50 in smokers; range 45-60) Menstrual history (shorter, longer or missed cycles) Physical exam none needed Laboratory tests generally none needed FSH > 30pg/ml confirmatory But FSH often normal in early menopause transition
Diagnosis of Hot Flushes Usually clear from history Differential diagnosis Alcohol consumption Carcinoid Dumping syndrome Hyperthyroidism Narcotic withdrawal Pheochromocytoma Medications - nitrates, niacin, gonadotropinreleasing hormone agonists, antiestrogens Estrogen Relieves Hot Flushes in Hot Flushes Placebo conjugated estrogens 0.625 mg plus alone MPA (cyc) MPA (cont) P (cyc) Greendale (PEPI), Obst Gynecol 1998
Treatment of Hot Flushes Estrogen Daily Dose % in HF 1 Oral CEE 0.625 0.45 0.3 2 Oral E 2 1.0 0.5 0.25 TD E 2 0.05 3 0.025 3 0.014 4 94 78 78 89 79 72 96 86 55 Estrogen effective - All preparations - Any route - Dose dependent Placebo - 30-50% reduction 1 Utian, Fertil Steril, 2001; 2 Notelovitz, Obstet Gynecol, 2000; 3 Utain, Am J Obst Gyn, 1999; 4 Bachmann, Obstet Gynecol, 2007 Side Effects of Estrogen Treatment Breast tenderness Endometrial hyperplasia Headache Bleeding Percent increase in risk of uterine cancer Years of Estrogen Use *Grady, Obstet Gynecol, 1995
Progestin Must be Added to Estrogen to Prevent Endometrial Cancer Any progestin effective Oral, transdermal, or vaginal route Preparations medroxyprogesterone acetate norethindrone micronized progesterone Side effects More breast tenderness Uterine Bleeding Probable increased risk of adverse events Approaches to Adding Progestin Cyclic/sequential Estrogen given every day Progestin added 10 or 14 days/mo (or Q 3-4 mo) Causes cyclic, menstrual-like bleeding Continuous/daily Estrogen given every day Progestin given at ½ dose every day Causes erratic bleeding in the first 6 to 12 months of use; subsequently amenorrhea Side effects - more breast tenderness, bleeding, probable increased risk of events Estrogen and progestin can be given separately or as combination preparation
Estrogen: Newer Regimens and Preparations Lower doses CE - 0.3, 0.45mg E 2-0.25mg New routes of delivery vaginal rings (Estring, Femring) skin gels (EstroGel) TD E 2-0.014, 0.025mg Use lowest dose of estrogen adequate to control symptoms Dose of progestin related to estrogen * See handout Newer Regimens and Preparations Long cycle progestin use 14 days every 3 to 6 months Vaginal gel (Prochieve) New combination pills and patches * See handout
Bioidentical Hormones Hormones identical to endogenous Often = pharmacy compounding 17β-estradiol, "plant-derived, natural, Goal: targeted level of hormones in the body Limited evaluation of safety and efficacy Estrone, estradiol, progesterone (available in FDAapproved manufactured products and as pharmacycompounded products Estriol (available in Europe, not approved in US) Expected to have the same risks and benefits of comparable approved drugs Progesterone may have improved safety profile Risks and Benefits of Hormone Therapy Two decades ago, observational studies suggested that hormone therapy reduced risk fracture heart disease increased risk breast cancer If true, hormone therapy would be beneficial on balance for most women Grady, Ann Intern Med, 1992
The Last Decade Evidence from randomized trials Alternatives treatments for fracture prevention prevention of coronary events treatment of menopausal symptoms Women s Health Initiative Randomized Trials 2 NIH-funded concurrent randomized trials in postmenopausal women uterus - CE+MPA vs. placebo (16,606) no uterus - CE vs. placebo (10,739) Multiple outcomes Planned follow-up 9 years Both trials stopped early due to lack of benefit or harm
What did the WHI trials show? 1. No increased risk of breast cancer 2. No decreased risk of CHD 3. Increased risk of VTE 4. All of the above 5. It s complicated 6. The trials were worthless WHI Results Relative Risks WHI E+P 1 WHI E only 2 CHD events 1.3* 0.9 Stroke 1.4* 1.4* Pulmonary embolism 2.1* 1.3 Breast cancer 1.3* 0.8 Colon cancer 0.6* 1.0 Hip Fracture 0.7* 0.6* Death 1.0 1.0 1 Rossouw, JAMA, 2002 2 WHI Steering Committee, JAMA 2004 *p-value <.05
Adverse Effects of Hormone Therapy Risk per 1000/year Harm E+P 1 Estrogen 2 CHD + 0.7* - Stroke + 0.8* +1.2* Breast cancer + 0.8* - Pulm. embolus + 0.8* Benefit Hip fracture - 0.5* -0.6* Colorectal cancer -0.6* - Net bad events +2.0* +0.6 1 Rossouw, JAMA, 2002 2 WHI Steering Committee, JAMA 2004 * p <.05 Endocrine Society 2010
Net Effect of Hormone Therapy is Harm Risk is Small for Short-term Use No role for prevention Estrogen only 0.6/1000 bad outcomes each year 3/1000 or 1/300 for 5 years of treatment Estrogen plus progestin 2/1000 bad outcomes each year 10/1000 or 1/100 for 5 years of treatment Timing hypothesis Possibly no increased CHD risk among women within 10 years of menopause 1 But other harms still present 2 1 Rossouw, JAMA, 2007 2 Prentice, Am J Epidemiol, 2009 Hormone related indicators of the risk of breast cancer ASRM Practice Committee Report 2008
Applying Risks from WHI to Symptomatic Women Women in WHI averaged 63 years old Women with menopausal symptoms generally 45 to 55 Disease rates lower in younger women Relative risks have less impact Estimated Risks of Hormone Therapy in Symptomatic Women Assume treating women in early 50s Unopposed estrogen.8/10,000 per year of treatment* 4/10,000 or 1/2500 for 5 years Estrogen plus progestin 1.6/1000 per year of treatment* 8/1000 or 1/150 for 5 years Risks are small for individual woman, but major public health impact if millions of users *Grady, NEJM, 2006
Prevention of Osteoporotic Fractures Harms seen in WHI clearly apply Women in WHI averaged 63 years old Women treated to prevent osteoporotic fractures are generally older Long-term treatment is required Estrogen should not be first-line therapy Prefer bisphosphonates or other drugs unless contraindications Hormone Therapy for Hot Flushes Given net effect of hormone therapy is harm and purpose is to control symptoms Use lowest dose that controls symptoms* Stop therapy when symptoms resolve* Contraindications Breast cancer or high risk of breast cancer Deep vein thrombosis or high risk Transdermal estrogen probably safer Active liver or gallbladder disease *FDA; American College of Obstetrics and Gynecology; North American Menopause Society
Symptomatic Treatment Given that net effect of hormone therapy is harm, treatment should be lowest dose of Estrogen and Progestin TD E2 0.014mg/d Standard dose Q3-4 mo oral E2 0.25 mg - MPA 5mg x 14 d CEE - 0.3 mg - MPA 10mg x 10 d - progesterone 200mg x 14 d - shortest time possible FDA; American College of Obstetrics and Gynecology; North American Menopause Society How long do hot flushes last? 1. A few months 2. A few years 3. Average of 8 years 4. Average of 15 years
Natural History of Hot Flushes In many women, resolve in a few years Mean duration 8 years In 10-15%, persist into late life Course variable, unpredictable Hormones for Hot Flashes Estrogen +/- progestin very effective most women with hot flashes are young hot flashes usually resolve in a few years Risk of bad outcomes is small, especially with unopposed estrogen
Endocrine Society 2010 Stopping Hormone Therapy Determine if symptoms have resolved Stop therapy every 6 months to 1 year If bothersome symptoms, recur resume After 5 years or so on therapy, if still symptomatic, attempt taper Dose taper Day taper For severe symptoms, long-term continuation of HT is reasonable
Hot Flushes: Alternatives to Estrogen Lifestyle Changes Lower ambient temperature* Dress in layers All kinds of other amazing things *Kronenberg, J Therm Biol, 1992
Alternative Therapies Possibly effective (pilots and small trials) Paced respiration Restorative yoga Mixed/poor evidence Acupuncture Exercise (worsened hot flashes in 1 trial) Not effective Homeopathy Magnets Herbs and Supplements Slightly effective Vitamin E 800 IU QD ( 1 HF/day) Mixed/poor evidence Black cohosh Phytoestrogens No benefit Chinese herbs (so far) Dong quai Evening primrose Ginseng Red Clover No data Chasteberry Licorice Wild yam
Other Hormones % Reduction Estrogens 55-95% Tibolone 1.25-5mg* 80-95% Megestrol 20 mg BID 75% MPA 20 mg BID 75% Placebo 30-50% * Not available in the US Other Drugs % Reduction Antidepressants 50-65% - citalopram (celexa) 30mg:1- trial - - Escitalopram (lexapro) 20 mg: 1+ trial + - Fluoxetine (prozac) 20-30mg:1+/1- trial +/- - Paroxetine (paxil) 12.5-25mgCR/20 mg:2 + trials ++ - Venlafaxine (effexor) 37.5-75 mg:1+/1? trial +/- Gabapentin 300-2400 mg: 4+ trials 50% Clonidine mixed evidence 30% Placebo 20-50%
Treatment of Hot Flushes Mild symptoms Lifestyle change Tolerance Moderate symptoms Low dose estrogen+/-progestin Paroxetine or gabapentin Severe symptoms Moderate dose estrogen +/- progestin Taper and/or stop as symptoms improve Case 1 Ms. HF could try lifestyle changes or nonhormone treatment, but she likely needs hormone therapy (unless contraindicated) - Give estrogen alone if no uterus Prefer estradiol? Transdermal? - Add a progestin if she has a uterus - Lowest dose that relieves symptoms - Try stopping every 6 months
Menopausal Vaginal Symptoms Vaginal symptoms Dryness Itching - Discomfort - Dyspareunia Prevalence 30% in early menopause 50% in late menopause Unlike hot flushes, symptoms generally do not resolve Etiology of Vaginal Symptoms Changes in symptomatic women Epithelial cells more immature Decreased blood flow and secretions Hyalinization of collagen Fragmentation of elastin Vaginal fluid less acidic (ph > 6.0) Enteric organisms proliferate Etiology estrogen deficiency?
Evaluation of Vaginal Symptoms Pelvic examination Pallor, dryness, decreased rugosity of vaginal mucosa (vaginal atrophy) Rule out other causes of symptoms infection trauma Laboratory evaluation - none Treatment of Vaginal Symptoms Estrogens 80 to 100% effective Vaginal preparations preferred (HANDOUT) Provide low systemic dose of estrogen Generally few side effects Do not need added progestin* Systemic estrogen less effective Might be adequate, esp. if also needs treatment for hot flushes *Suckling, Cochrane Database Syst Rev, 2003
Treatment of Vaginal Symptoms Vaginal moisturizers Replens (other brands not tested) Bioadhesive polycarbophil-based As effective as estrogen vaginal cream Vaginal lubricants Astroglide, etc. Short-acting lubricants Use prior to intercourse to relieve dyspareunia *Suckling, Cochrane Database Syst Rev, 2003 Nachtigall, Fertil Steril, 1994 Case 2 Ms VA will probably get relief by using either a vaginal estrogen or a moisturizer such as Replens Estrogen cream or tablet daily for 2 weeks, then 2-3 times/week Replens 3 times/week
Summary Hot flushes and night sweats Treat based on severity of symptoms Hormones most effective treatment Risk for adverse events is small Use lowest effective dose Stop when symptoms resolve Vaginal symptoms Vaginal estrogen or Replens Depressive symptoms Treat as for depression
Case 1 Ms HF: A 51 yo lawyer with frequent hot flushes, night sweats, and trouble sleeping Symptoms are ruining her life Last menstrual period 6 months ago What would you suggest? 1. Wear layers, keep the windows open the symptoms will resolve with time 2. Estrogen (with a progestin if she has a uterus) 3. Anti-depressant 4. Gabapentin 5. More tofu in her diet
Case 2 Ms VA: A 60 yo photographer complaining of vaginal dryness, itching and dyspareunia Symptoms are ruining her sex life Last menstrual period age 49 What would you suggest? 1. Estrogen cream 2. Vaginal moisturizer 3. Vaginal lubricant 4. Just give it up