Menopause WebcastAHSC Arizona Health Sciences Center PowerPoint Presentation

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Menopause and Your Health Celia P. Valenzuela, MD Assistant Professor Obstetrics and Gynecology University of Arizona cpvalenz@email.arizona.edu

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Understand hormonal and physical changes that occur with menopause Understand risks and benefits associated with postmenopausal hormone therapy Learn about alternative therapies for treatment of menopausal symptoms Educational Objectives ¡Vida! Educational Series - Promoting Good Health

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Midlife Event Viewed Negatively

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Negative experiences coincide Onset of major illness or disability in self or loved ones Retirement/financial insecurity Care needed for aging parents Empty nest syndrome Physicians Majority of healthy/happy patients do not seek help Conflicting and lack of data Time consuming Midlife Event Viewed Negatively

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12 months of amenorrhea (no menses) Average age 51 Derived from the Greek words “men” (month) and “pausis” (cessation) Primary ovarian function stops Marks the permanent end of fertility What is Menopause?

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Transition Change from normal ovulatory cycles to complete cessation of menses Marked by menstrual irregularity May begin years prior to menopause Onset of menopausal symptoms Perimenopause

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The Reproductive Cycle

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Anovulatory cycles can lead to hyperplasia Prolonged, heavy or frequent bleeding should raise red flag Options for controlling bleeding (and protecting endometrium against hyperplasia) Low dose birth control pills Cyclic progesterone Mirena intrauterine device Ablation may also be used to control bleeding (need EMB first) Perimenopausal Bleeding

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Changes in Hormone Patterns

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Inhibin levels fall Produced by granulosa cells Decrease may be from declining number of follicles or reduced quality/capacity of aging follicles Speroff Serum FSH levels rise Slight increase in estradiol levels Changes in Hormone Patterns

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Cycle variability increases Hormone levels fluctuate FSH and estradiol may return to premenopausal ranges After menopause, ovary no longer secretes estradiol – continues to produce androgens (under continued stimulation of LH) Elevated levels of FSH and LH = evidence of ovarian failure Speroff Changes in Hormone Patterns

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Perimenopause

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Postmenopausal hormone (HRT) regimens do not suppress ovulation Oral contraceptive that contains 20 micrograms estrogen provides effective contraception Even lowest dose OCP provides 4x estrogen dose in standard (HRT) Low Dose Birth Control Pills vs Hormone Replacement Therapy

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Hot flashes Sleep disturbances Vaginal dryness Mood changes Difficulty concentrating Memory impairment Bladder irritability/urgency Changes in balance Decreased interest in sex, possibly decreased response to sexual stimulation Menopausal Symptoms

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Vasomotor Symptoms Most often begin in perimenopause Sudden onset reddening of the skin (head/neck/chest), feeling of intense body heat, profuse perspiration Speroff Intervals vary (minutes to hours) More frequent and severe at night Generally stop spontaneously w/in few years, may persist for many years 12-15 % of women in 60’s 9% of women after age 70 Casper

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Other Causes to Consider Thyroid disorders Pheochromocytoma Leukemia Cancer Infection

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Estrogen initially prescribed as treatment for vasomotor symptoms in 1960’s Use declined in mid 1970’s secondary to link to endometrial cancer Use increased again in 1980’s when addition of progestin determined to be protective Indications expanded to include prevention of diseases of aging A Bit of History: Shifren JL, Schiff I. Role of Hormone Therapy in the Management of Menopause. Obstetrics and Gynecology; 2010: 115, 4: 839-855.

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Observational study > 70,000 initially healthy postmenopausal women Decrease in coronary events in women undergoing hormone therapy Women aged 35-55 at baseline Nurse’s Health Study

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Oral estrogen lowers: LDL Lipoprotein(a) Glucose Insulin Homocysteine levels Oxidation of LDL Increases HDL Estrogen Benefits

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Estrogen Benefits One HT study of women taking 0.625 or 1.25 mg of conjugated equine estrogens with 5 mg medroxyprogesterone daily showed that total and low density lipoprotein cholesterol were reduced to nearly the same extent as that of women treated with 10 mg simvastatin daily. HDL was increased to a greater extent than did simvastatin in this study.Harman

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Estrogen Risks Estrogen also increases: Triglycerides Coagulation factors C-reactive protein (inflammatory risk factor for CHD) Certain progestogens offset some of estrogen’s benefitsManson

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Organized by NIH in 1992 Set of clinical trials Primarily a trial of primary prevention of CV disease Randomized, double blind, placebo controlled 27,347 postmenopausal women 40 US clinical centers Hormone Therapy - WHI

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Combined estrogen-progestin arm 0.625mg conjugated estrogens and 2.5mg medroxyprogesterone Randomized 16,608 women into either tx or placebo May 2002, Data and Safety Monitoring Board recommended discontinuation of this arm Statistically significant increase in breast cancer Increase in CV events (CHD, stroke, venous TE) Hormone Therapy - WHI

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Estrogen only arm 0.625 mg conjugated estrogens Randomized 10,739 women (s/p hyst) Feb 2004, NIH canceled study Increased risk of stroke similar to combined arm No increase or decrease in CHD Trend towards increased risk of probable dementia and/or mild cognitive impairment Reduction in hip fractures No increase in breast cancer Hormone Therapy - WHI

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WHI – largest and longest trial of postmenopausal women using hormone therapy (5-7 years) Based on previous observational studies, prevention of chronic conditions of aging in women, including heart disease, was expected to be demonstrated Instead found that hormones were associated with a greater risk of CHD Hormone Therapy - WHI

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Mean age 63 Fewer patients in the estrogen only arm (decreased statistical power) Women with significant menopausal symptoms were excluded (to limit drop out rate) – led to fewer women close to their age at menopause Diagnostic bias possibility? 40.5 percent of estrogen-progesterone group, 6.8 of placebo group, unblinded secondary to vaginal bleeding Unblinding not a problem in estrogen only arm Speroff Problems with WHI

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Heart and Estrogen/Progestin Replacement Study Secondary Prevention of CV disease 2763 postmenopausal women with established CHD were randomized to placebo or continuous E/P Mean baseline age 67 No reduction in the risk of CHD events HERS Trial

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Differences in study participant age Most observational studies – started taking around time of menopause. WHI – average age 63 Timing Hypothesis HERS and WHI trials failed to show cardioprotection because these older women already had atherosclerosis Suggests that estrogen therapy is bad for atherosclerotic arteries but prevents atherosclerosis if begun early enoughBarrett-Conner Why the Discrepancy?

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Harman SM. Estrogen Replacement in Menopausal Women: Recent and Current Prospective Studies, the WHI and the KEEPS. Gender Medicine; 2006: 3,4: 254-269.

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Secondary analysis of data stratified based on age and time from menopause No increased risk seen in women between 50-59 or in those within 10 years of menopause (underpowered to reach statistical significance) Stroke increased regardless of age and years since menopause Hazard ratios for breast cancer and total cancer higher in women who initiated hormone therapy soon after menopause (both regimens) Reanalysis of Data from WHI Shifren JL, Schiff I. Prentice RL, et al. Benefits and risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause. American Journal of Epidiomology 2009; 170: 12-23Role of Hormone Therapy in the Management of Menopause. Obstetrics and Gynecology; 2010: 115, 4: 839-855. .

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WHI Coronary-Artery Calcium Study Evaluated 1,064 women who were previously enrolled in the conjugated equine estrogen arm of WHI – age 50-59 at randomization Used Cardiac CT to determine the degree of coronary-artery calcium burden Atherosclerotic plaques are associated with future CHD risk Imaging was conducted at 28 of 40 centers after a mean of 7.4 years of treatment and 1.3 years after the trial was completed. Coronary artery calcium scores were measured at a central reading center without knowledge of randomization status Overall distribution of coronary-artery calcification scores were lower among those receiving CEE compared with placeboManson

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Is Transdermal Better?

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Oral estrogen has greater effect on liver – first pass effect Absorbed through intestine, then passes through liver Increases liver production of Sex steroid binding globulins Triglycerides HDL Clotting factors Liver is not normally exposed to such high levels of estrogen, except during pregnancy Transdermal Estrogen

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Ongoing Studies –KEEPS Kronos Early Estrogen Prevention Study Women aged 42 to 58 years At least 6 months, no more than 36 months postmenopausal Randomized to oral CEE 0.45, transdermal 17B-estradiol 0.05 mg, or placebo (Micronized progesterone given orally 12 days/month). Primary prevention trial looking at intermediate markers of CHD Intima-media thickness of the carotid artery Accruel of coronary artery calcium (Cardiac CT) Variety of risk factors including lipids, inflammatory factors, coagulation indicators

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Ongoing Studies – ELITE Early versus Late Intervention Trial with Estradiol 643 postmenopausal women randomized according to years since menopause (<6 or >10) To receive either 1 mg oral estradiol or placebo in double blind fashion Ultrasonography used to measure the rate of change in thickness of the carotid artery Cardiac CT to measure coronary artery calcium

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For women with moderate to severe vasomotor symptoms, depending on individual risk, and patient’s willingness to accept risk, use the lowest dose of estrogen (with progesterone, if uterus intact) effective for the shortest amount of time possible. What Now?

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Risk of Breast Cancer: For estrogen/progesterone therapy, time is limited by the increased risk of breast cancer that is seen with more than 3-5 years of use For estrogen only, no sign of an increased risk of breast cancer was seen during an average of 7 years of treatment Risk of Heart Disease/Stroke: Most healthy women below age 60 will not have an increased risk of heart disease with hormone therapy In women below age 60, risks of stroke and blood clots are less than 1/1000 women per year. How Long?

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Abrupt withdrawal increases return of moderate to severe symptoms Tapering dose of hormones lowers risk of recurrent symptoms Weaning off Decrease to lowest dose first Decrease by one pill per week, or Skip 1 day, then 2 days, etc Slower tapering may benefit women with recurrence Cessation of Hormone Therapy

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Premarin – conjugated equine estrogens Comprised mostly of estrone sulfate 10 estrogens total Doses: 1.25 mg, 0.625 mg, 0.45 mg, 0.3 mg Cenestin – conjugated estrogens derived from plant source Similar to premarin Contains 9 estrogens Enjuvia – also conjugated estrogens derived from plant source Estrogen Preparations

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Estratab, Menest – esterified estrogens derived from plant source Result in serum estradiol and estrone levels similar to premarin Ogen – naturally derived, purified estrone sulfate Estrace – micronized preparation of estradiol Estratest – esterified estrogens and methyltestosterone Estrogen Preparations

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Prempro FemHrt ethinyl estradiol (potent synthetic estrogen used primarily in OCPs) with norethindrone acetate Doses = 2.5 mcg/0.5 mg and 5 mcg/1 mg) Angeliq 1 mg estradiol/ 0.5 mg drospirenone Activella 1 mg estradiol/ 0.5mg norethindrone Oral Combination Preparations

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Contain 17-beta estradiol Doses range from 25 to 100 mcg/day 50 mcg/day is equivalent to 0.625 mg of conjugated estrogen Vivelle-dot 0.025, 0.0375, 0.05, 0.075, 0.1/day patch Menostar – ultra low dose, 14 mcg/day addition of progesterone may be two 14 day cycles/year Transdermal Estrogen

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Combipatch 50 mcg/day 17 beta estradiol 0.14 or 0.25 mg/day norethindrone acetate Climara Pro 45 mcg/day 17 beta estradiol 0.15 mg/day levonorgestrel Combined Patches

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Estrasorb (estradiol emulsion) 0.05 mg/day estradiol EstroGel 0.75 mg/day Divigel 1 mg estradiol/g (apply 0.25g) Elestrin 0.87 g gel provides 0.52 mg estradiol Evamist 1.53 mg/spray Topical Estradiol Preparations

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Prometrium – natural micronized progesterone Medroxyprogesterone Drosperinone Megestrol acetate Testosterone derivatives (have some weak andronergic actions) Norethindrone Norgestrel levonorgestrel Progestin Therapy alone may also relieve hot flushes Progesterone Preparations

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Daily progesterone 10-14 days Q month Long-cycle Q3-6 months Insufficient evidence regarding endometrial safety NAMS Progesterone is a large molecule, does not absorb well through skin Protecting the Endometrium

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How do you choose?!?!

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Transdermal may be more convenient, avoids liver first pass effect Combined may be more convenient Plant derived: Estrace, Vivelle dot, Climara, Prometrium, Cenestin May need to change route or dose based on patients symptoms (eg breast tenderness, bleeding) How do you choose?!?!

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Cost (Costco pharmacy) Premarin - $180 for 100 tablets Estrace - $215 for 100 tablets Estradiol (gen) – $10 for 100 Medroxyprogesterone - $10 for 100 Fem-hrt - $200 for 84 tablets Vivelle-dot – $176 for 24 Estradiol patch – $100 for 12 How do you choose?!?!

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0.625 mg of conjugated estrogens, esterified estrogens, estrone sulfate 1 mg of micronized estradiol 0.05 mg of transdermal estradiol 5 mcg of ethinyl estradiol What dose ?! Estrogen Equivalents

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Anticonvulsants increase hepatic clearance of estrogen Estrogen may increase T4 requirements Acute alcohol ingestion increases serum estradiol End stage renal disease – higher serum estradiol levels Martin Alterations of Estrogen Metabolim

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Lifestyle modifications Keeping core temperature cool Regular exercise, weight loss Relaxation therapy/stress management/reflexology Isoflavone supplements: Soy, red clover, black cohosh Acupuncture Black cohosh may have estrogenic effect on breast – do not use in breast cancer pt Alternative Therapies

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Alternatives: SSRIs Venlafaxine (effexor) Fluoxetine (prozac) Sertraline (zoloft) Citalopram (celexa) Paroxetine (paxil) Desvenlafaxine (pristiq) Escitalopram (lexapro) Duloxetine (cymbalta)

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Copyright 2011 Adis Data Information BV. Published by Adis International. 2 Non-Hormonal Treatment Strategies for Vasomotor Symptoms: A Critical Review. Hall, Elise; Frey, Benicio; Soares, Claudio Drugs. 71(3):287-304, February 12, 2011. DOI: 10.2165/11585360-000000000-00000 Table I . Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors for treatment of vasomotor symptoms (VMS)AEs = adverse events; BDI = Beck Depression Inventory; CEE = conjugated equine estrogen; GCS = Greene Climacteric Scale; HAM-D = Hamilton Depression Rating Scale; HRT = hormone replacement therapy; MADRS = Montgomery-Asberg Depression Rating Scale; ol = open-label; OPL = open-label, placebo lead-in; RAC = randomized, active comparator; RPL = randomized, placebo-controlled.

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Venlafaxine (effexor) Selectively inhibits both serotonin and NE reuptake No benefit seen above 75 mg SE = dry mouth, nausea, insomnia, sexual dysfunction Paroxetine (paxil) Avoid in women receiving tamoxifen – reduces formation of active metabolites Alternatives: SSRIs

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Gabapentin reduces frequency of hot flashes Large study 420 women with breast cancer – 3 groups, randomly assigned, 8 wks Placebo – decrease 15% (hot flash score) 300 mg/d – decrease 31% 900 mg/d – decrease 46% Rapkin Other studies have shown similar results Alternatives: Gabapentin

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Somnolence = common side effect Dose of 300 to 600 HS = useful for relieving hot flashes that awaken patients from sleep HS dosing also reduces other side effects Casper Other SE = dizziness, disorientation Alternatives: Gabapentin

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Alpha-2 adrenergic agonist Reduces central noradrenergic activityRapkin Modest efficacy May be considered for women with HTN Weekly patch 0.1 mg/day May increase to 0.2 or 0.3 mg/day Side effects: dry mouth, dizziness, constipation, sedation Abrupt cessation may cause rebound HTN Alternatives: Clonidine

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“My friend said I should use compounded bioidentical hormones.” Bioidentical Hormones

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Patients undergo consultation with pharmacologist Have hormone levels checked by serum or saliva Tend to have doses “tailored” based on hormone testing Pharmacologist sends script to health care provider for signature Compounded Bioidentical Hormones

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Are plant-derived hormones that are biochemically similar or identical to those produced by the body or ovaries Begin as soy products or wild yams, get converted to different hormones in the laboratory. Some use this term interchangeably between compounded bioidentical hormones – this is wrong Bioidentical Hormones

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Compounding is the combining or altering of ingredients by a pharmacist to produce a drug tailored to an individual patient’s special medical needs - for example, by removing a dye or preservative in response to a patient allergy. Drugs that pharmacists compound are not FDA approved. One study done by the FDA found that 30% of compounded products failed one or more standard quality tests performed. Compounded Medications

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Risk for over-treating, increasing risks Expensive, generally not covered by health insurances Often promoted by individuals outside medical community Compounded Bioidentical Hormones

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Compounded bioidentical hormones are not FDA regulated (not tested for purity, potency, efficacy, safety) No official labeling, exempt from including the contraindications and warnings required by the FDA Many prescription hormones approved by the FDA contain bioidentical hormones Estrace (vaginal and oral) Climara Estraderm Estragel Estrasorb Estring Femring Vagifem Prometrium Bioidentical Hormones

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ACOG North American Menopause Society (NAMS) The Endocrine Society All agree that Compounded hormones are not safer Issues regarding purity, potency, and quality are a concern Compounded Bioidentical Hormones

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NAMS – does not recommend saliva testing to determine hormone levels Endocrine Society – “salivary hormone tests are inaccurate and should not be considered reliable measures of hormones in the body” ACOG No biologically meaningful relationship between salivary sex steroidal hormone concentrations and free serum hormone levels Salivary hormone levels vary with diet, time of day, and other variables Pinkerton Saliva Testing?

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Don’t check Evidence-based guidelines recommend individualization of hormone therapy based on symptoms, not hormone levels Lowest effective dose for shortest time possible! Serum Hormone Levels

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Maintains collagen content – effects thickness and elasticity Maintains mucopolysaccharides and hyaluronic acid – keep epithelial surfaces moist Maintains optimal blood flow Keeps epithelium rich in glycogen Glycogen = substrate for lactobacilli, which convert glucose to lactic acid (creating acidic pH) Acidic environment protects against vaginal and urinary tract infections Effect of Estrogen on Vaginal Tissue

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Without Estrogen Vagina loses collagen, adipose tissue and ability to retain H20 Labia and vulva lose fullness Blood vessels narrow and secretions from sebaceous glands decrease Vaginal opening may narrow Vaginal length may shorten

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Without Estrogen Surface epithelium loses outer fibrous layer, decreases ratio of superficial to parabasal cells.

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With loss of glycogen, pH increases (generally > 5) Environment less hospitable for lactobacilli More susceptible to pathogens from skin and rectum Urogenital problems Urgency Dysuria Abacterial urethritis Recurrent UTIs Urethral caruncles Vaginal Atrophy

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Vaginal dryness Pruritis (itching) Discharge – yellow, malodorous Dyspareunia (painful intercourse) Vaginal bleeding or spotting Unlike hot flushes, symptoms do not improve with time Most Common Complaints

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Estrogen replacement Sytemic and local are effective Low vaginal doses usually do not reach serum levels sufficient to create systemic side effects (endometrial stimulation) Bachman Creams, rings, tablets similarly effective Vaginal Atrophy – Treatment

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Premarin 0.625 mg/g (conjugated estrogens) ½ g vaginally x 2 weeks, then 2x/week Estrace 100 mcg/g estradiol ½ g vaginally x 2 weeks, then 2x/week Vagifem 25 mcg estradiol 10 mcg tablets approved in 2010 Vaginal Estrogens

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Estring Silastic ring impregnated with estradiol 6-9 mcg estradiol daily x 3 months Femring 50 – 100 mcg/day Suitable for tx of vasomotor and vaginal atrophy Vaginal Estrogens

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Should you add a progestin?

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Low doses do not increase serum estrone or estradiol significantly (studies have demonstrated levels remain in postmenopausal range) Higher doses raise serum estrogen concentrations to as high as 500 pg/mL Bachman Low doses: 0.3 mg of premarin cream 2x/wk (1/2 g) 50 mcg of estrace cream 2x/wk (1/2 g) 25 mcg of vagifem 2x/wk Add a progestin when levels above this are used Should you add a progestin?

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12 week study on breast cancer patients taking aromatase inhibitor and vagifem 25mcg Suppression of serum estradiol levels achieved were reversed at 2 wks post starting vagifem For patients with severe symptoms, not on aromatase inhibitor, failed alternatives  counsel, discuss with her oncologist What about patients with Breast Cancer?

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Sexual activity Improves blood supply Preserves elasticity Prevents introital narrowing Lubricants K-Y Jelly Astroglide K-Y Liquid beads (silicone based) Vaginal Atrophy - Alternatives

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Replens Long-acting moisturizer Polcarbophil-based polymer, binds to vaginal epithelium, releases H20, produces moist film over vaginal tissue May restore normal vagina pH, does not affect cytology K-Y Silk-E Feminease Contains mineral oil, glycerin, yerba santa Vaginal Atrophy - Alternatives

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Weight gain Decrease bone mineral density Physical Changes of Menopause

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Hair changes: Thinning of hair on scalp Unwanted hair on face Skin: 30% of skin collagen is lost during the 1st 5 years following menopause, followed by an average decline of 2%/menopausal year (statistics similar to bone loss) Skin becomes drier Physical Changes of Menopause

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Sleep studies suggest: Nocturnal hot flashes more common during 1st 4 h of sleep REM in subsequent 4 h suppresses hot flashes, arousals and awakenings Sleep is affected by anxiety and depression symptoms Primary sleep disorders = common Report of 102 women ages 44-56 who reported sleep disturbances, 53% had sleep apnea, restless leg syndrome or both Casper Sleep Disturbances

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Menopause is defined as 12 months without periods Symptoms can start up to 10 years prior Best Candidates for hormone therapy are women who: Are in their 50’s or younger Had their last menstrual period within the last 3 years Have moderate to severe symptoms Use lowest effective doses of hormones, for shortest duration possible Take individualized risk factors into consideration (high blood pressure, diabetes, smoking, excess weight, personal or family h/o blood clots) Be wary of compounded hormones Summary

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Patient Resources menopause.org North American Menopause Society hormone.org/MenopauseMap Endocrine Society acog.org/For_Patients American Congress of Obstetrics and Gynecology

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Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanik ML. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years since Menopause. JAMA, April 4, 2007. 297 (13): 1465-1426. Bachman, G; Santen, RJ. Diagnosis and Treatment of vaginal atrophy. UptoDate. Available at uptodate.com. Referenced 01/27/09. Stuenkel, CA. Top 10 Menopause Stories of 2008. Menopause Management, Women’s health trough midlife and beyond. 2009 January/February;18(1):12-19. Rapkin, AJ. Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J of Obstetrics and Gynecology 2007 Feb: 97-106. Speroff, L; Fritz, M. Clinical Gynecologic Endocrinology and Infertility. 2005 Lippincott Williams & Wilkins. Chapters 17 and 18. Evans, ML; Pritts, E; Vittinghoff, E, et al. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol 2005: 105:161 Harman SM. Estrogen Replacement in Menopausal Women: Recent and Current Prospective Studies, the WHI and the KEEPS. Gender Medicine; 2006: 3,4: 254-269. References

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Pal L, Manson JE. Editorial: The Women’s Health Initiative: an unforgettable decade. Menopause: The Journal of The North American Menopause Society. 2012 19;6:597-599. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society; Menopause: The Hourna of the North American Menopause Society; 14(2): 168-182. Manson, JE, Bassuk, SS. Invited Commentary: Hormone Therapy and Risk of Coronary Heart Disease – Why renew the Focus on the Early Years of Menopause? American Journal of Epidemiology; 166(5): 511-517. Hormone Therapy and Heart Disease. ACOG Committee Opinion, No 420, November 2008. Compounded Bioidentical Hormones. ACOG Committee Opinion, No 32, November 2005. Hall e, Frey BN, Soares CN. Non-Hormonal Treatment Strategies for Vasomotor Symptoms, A Critical Review. Drugs 2011: 71 (3): 287-304. Manson Je, et al. Estrogen Therapy and Coronary-Artery Calcification. The New England Journal of Medicine 2007 356;25:2591-2602. Barrett-Connor E. Hormones and Heart Disease in Women: The Timing Hypothesis (commentary). American Journal of Epidemiology 2007;166: 506-510. Kaunitz AM. Editorial: Transdermal and Vaginal Estradiol for the Treatment of Menopausal Symptoms: the Nuts and Bolts. Menopause: The Journal of the North American Menopause Society. 2012 19;6: 602-603 References

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Prentice RL, et al. Benefits and risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause. American Journal of Epidiomology 2009; 170: 12-23. Shifren JL, Schiff I. Role of Hormone Therapy in the Management of Menopause. Obstetrics and Gynecology; 2010: 115, 4: 839-855. Simon JA. Editorial: Vulvovaginal atrophy: new and upcoming approaches. Menopause: The Journal of the North American Menopause Society 2009; 16, 1: 5-7. Stearns, V; Beebe, Kl, Iyengar, M; Dube, E. Paroxetine Contolled release I the treatment of menopausal hot flashes a rendomized control trial. JAMA 2003; 289: 2827. Casper, RF; Santen, RJ. Menopausal Hot Flashes. UpToDate; available on uptodate.com; Referenced 06/06/2012. Pinkerton, JV. Bioidentical Hormones. OBG Management; 2009, Jan; 21(1):43-52 Martin, KA; Barbieri, RL. Preparations for postmenopausal hormone therapy. UpToDate; available on uptodate.com; referenced 01/04/09 Menopause Practice, a Clinician’s Guide, 4th Edition. The North American Menopause Society. 2010. Mayfield Heights, Ohio. References

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Santoro, N. Symptoms of Menopause. Clinical Obstetrics and Gynecology;51(3): 539-548. Kalay, AE; Demir, B; Haberal, A; Kalay, M; Kandermir, O. Efficacy of citalpram on climacteric symptoms. Menopause: The Hourna of the North American Menopause Society; 14(2): 223-229. Freedman, RR. Menopause Sleep Disturbance. Menopause Management Women’s Health Through Midlife & Beyond. 2009 Jan/Feb (18(1): 9-11. References