Back to the Future: Applying New Evidence in Menopause Management Michael Policar, MD, MPH www.PolicarLectures.com

Topics To Be Discussed New information from the WHI The expanding range of treatments for managing menopausal symptoms Which treatments are available to your patient? Practice Recommendations How can your patient use these treatments safely, effectively, and conveniently?

NAMS Definitions Progestogen Progesterone or progestin (P) ET Estrogen (E) therapy EPT Combined E+P therapy HT Hormone therapy (ET and EPT) CC-EPT Continuous-combined E+P therapy - E+P given every day CS-EPT Continuous-sequential E+P therapy - E daily with P added on set sequence NAMS position statement. Menopause 2007.

The WHI Re-analyzed Act 1 Let’s Get This Out of the Way….

Background: HRT 1960-1980s Menopause seen as endocrine deficiency requiring hormone replacement therapy 1960s: successful oral contraceptive introduction “The Pill” freed women from fear of pregnancy HRT offered women freedom from fear of aging 1972: Forever Feminine by Robert A. Wilson, MD 1980s: Expanding uses of HRT Initially used to treat hot flashes, vaginal sxs Later uses…protection of bone and heart 5

Background: Late 1980s In 40 retrospective observational studies, both EPT and ET reduced the risk of heart attack by 50% Most studies included women in their 50s Women were self-selected for hormone use (or not); studies were subject to selection bias Conventional wisdom All women should use HT for heart protection, unless there was a reason not to do so Women with CVD risk factors, especially previous MI, stroke, HTN or diabetes, should use HT 7

Background:1990s 1990: Wyeth requested that FDA add labeling to HT products that included cardioprotection FDA insisted that RCTs be performed to prove that HT improved CVD outcomes vs. placebo Two RCTs initiated to evaluate cardioprotection HERS: secondary prevention trial WHI: primary prevention trial

HERS Study: 1998 Does EPT reduce MIs in women with CHD? 2,763 women randomized to CC-EPT or placebo Entry: MI, CABG, balloon angioplasty, + angiogram Menopausal, intact uterus, 44-80 years of age Average follow up: 4.1 years Study findings EPT had no value in reduction of MIs or CHD deaths More deaths in year 1; neutral thru year 8 Not seen in prior observational studies 3-fold increased risk of VTE events Hulley, JAMA 1998:280:605 9

Women’s Health Initiative (WHI): 2002 1993-2005: RCT with 17,000 women Postmenopausal women 50-79 years old 33%: 50-59 yrs old; 45%: 60-69 yo; 22% 70-79 yo Average age: 64 years old End points Primary prevention of MI and stroke Hip fracture, various cancers Treatment arms If uterus: CC-EPT (CEE+MPA) vs. placebo If no uterus: ET (CEE) vs. placebo 10

WHI: EPT Arm Study Results Released July 2002: Findings after 5 WHI: EPT Arm Study Results Released July 2002: Findings after 5.2 years Event RR Risk/10K/yr Benefit/10K/yr Heart attack 1.29 7 Stroke 1.41 8 Breast cancer 1.26 8 TE event 2.11 18 Colorectal CA 0.63 6 Hip fractures 0.66 5 Discontinued early, as “risks greater than benefits” 11

WHI : ET-Only Study Arm Released 2004: Findings after 7 years Outcome Change vs. Placebo Coronary heart disease No difference in risk Breast cancer No difference in risk Stroke Increased risk Hip fractures Decreased risk Dementia, cognitive Trend toward increased Change (> 65 years old) risk 14

WHI and HERS: The 2004 Take Home Message HT does not protect women from heart attacks over the long term …and actually may increase the risk of MI in the first year of HT use The rest is “specialty-specific” perception of benefit and risk 15

Was the WHI designed to evaluate the safety and efficacy of EPT in treating menopausal changes? The Women’s Health Initiative Was not a menopause study Was a drug study of the effect of hormones on CVD, cancer, fractures, and memory in older women (average 64 year old)

How Different Were WHI Findings Compared to Earlier Studies? Manson JE, Menopause 2006;13:139

WHI: HT and Risk of CV Disease by Age and Years Since Menopause Roussow JE. JAMA. 2007: Combined secondary analysis Age at HT initiation Heart attack Stroke Death from any cause 50–59 years ↓ 7% ↑ 13% ↓ 30% 60–69 years ↓ 2% ↑ 50% ↑ 5% 70–79 years ↑ 26% ↑ 21% ↑ 14% A combined secondary analysis of WHI studies to determine if age at initiation of HT affected cardiovascular risk was published in the Journal of the American Medical Association (JAMA) in 2007. Both arms of the WHI were combined for this analysis, which allowed for evaluation of more than 26,000 women. This secondary analysis revealed that women who initiated HT closer to the age of menopause had a significantly reduced risk of death from any cause compared to women who took placebo. Additionally, risk of heart attack was reduced in women receiving HT closer to the age of menopause, but not at a significant level. On the other hand, stroke risk was elevated for all groups regardless of years since menopause. “Women who initiated HT closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion* for statistical significance.” *Statistically significant defined as p<0.01.

WHI (EPT arm) Re-analyses Age vs. Years Since Menopause Age (years) 50–59 60–69 70–79 Years Since Menopause <10 10–19 20 1.27 1.05 1.44 0.89 1.22 1.71 Manson et al evaluated the risk of CHD in certain subgroups of the WHI, designated by factors such as age and years since menopause to determine whether women were at a higher or a lower risk for CHD with CEE/MPA compared with placebo, In this analysis, no significant interaction between age or years since menopause and treatment was observed (P = 0.36 for the age analysis and P = 0.33 for years-since-menopause analysis), although there was a numerical trend towards a higher risk with CEE/MPA use among those women with the longest times since menopause. While the investigators noted that the findings of the subgroup analyses should be interpreted with caution because of the small size of many of the subgroups as well as the large number of comparisons performed (approximately 36 tests were performed), these findings are consistent with accumulating data that the timing of initiation of HT in relation to the development of atherosclerosis is an important variable that may influence the potential risks and benefits of HT. Hypertension per se should not be considered contraindication to estrogen therapy since research shows that replacement doses of estrogen have little effect on blood pressure. The WHI combined estrogen-progestin trial noted only a small increase (1.5 mmHg) in systolic pressure compared with placebo.86 In the WHI trial of unopposed estrogen, a similar difference between the hormone and placebo groups of 1.1 mmHg was observed. References Manson JE, et al. N Engl J Med. 2003;349:523-34. Rossouw, JE, Anderson, GL, Prentice, RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321. Anderson, GL, Limacher, M, Assaf, AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701. Hazard Ratio for CHD Manson JE, et al. N Engl J Med. 2003;349:523-34 Manson JE, et al. N Engl J Med. 2003;349:523-34. 19

WHI: Estrogen and Major Health Outcomes in Women Under 60 Years of Age % difference in relative risk Events/ 10,000 WY of CEE therapy Total mortality -29 (0.46-1.11 -11 Coronary heart disease -37 (0.36-1.09) Stroke -11 (0.47-1.69 -2 New onset DM -12 (0.77-1.01) -14 Fracture -30 (0.59-0.83) -56 Breast cancer -18 (0.65-1.04) -8 VTE +37 (0.70-2.68) +4 Hodis HN, Mack WJ. Menopause Management 2008

The Unified Hypothesis 2005 WHI Phillips LS, Langer RD, Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertility and Sterility 2005; 83:558-66

Clinical Implications: Unified Hypothesis Mild cardioprotection Women in their early-mid 50s, who Initiate HT soon after menopause, with Few or no heart disease or stroke risk factors And who use estrogen-only regimens Increased heart disease risk Women in their mid-60s or later, who Initiate HT long after menopause, who have Heart disease or stroke risk factors And who use estrogen and progestin regimens

Benchmark HT Cardioprotection Studies Primary Prevention “Healthy women” Secondary Prevention Women with known heart disease Observational Studies Nurses Health Study Various small studies Randomized Clinical Trials WHI KEEPS HERS

Key Points: NAMS March 2007 Position Statement on Hormone Therapy The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 2007 Copyright 2007

HT and Coronary Heart Disease ET/EPT not recommended as single or primary indication for coronary protection in women of any age Data do not currently support EPT in secondary prevention of CHD NAMS position statement. Menopause 2007.

HT and Stroke Both ET and EPT appear to increase the risk of ischemic stroke in postmenopausal women No HT regimen should be used for the primary or secondary prevention of stroke HT should be avoided for women who have elevated baseline risk of stroke NAMS position statement. Menopause 2007.

HT and Venous Thromboembolism Significant increase in VTE risk in postmenopausal women using systemic HT Risk increased with both EPT and ET VTE risk appears during first 1-2 years after therapy initiation and decreases over time Transdermal 17ß-estradiol and oral therapies may have different risk Lower doses of oral estrogens may be safer than higher doses NAMS position statement. Menopause 2007.

EPT and Breast Cancer Risk Breast cancer risk increases with EPT use beyond 5 years Increased absolute risk in WHI is viewed as rare (4-6 additional invasive cancers/10,000 women/year when use EPT used for ≥ 5 yrs) Not clear whether risk differs between CC-EPT and CS-EPT NAMS position statement. Menopause 2007.

ET and Breast Cancer Risk (cont’d) Women in WHI’s ET arm had 8 fewer cases of invasive breast cancer/10,000 women/yr of ET use Available evidence suggests ET for < 5 years has little breast cancer risk impact Limited observational data suggest ET given longer than 15 years may increase risk NAMS position statement. Menopause 2007.

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Therapeutic Interventions Non-Hormonal Act 2 Therapeutic Interventions Non-Hormonal

General Health Recommendations Exercise: aerobic + strength training Reduction in hot flashes in some women Healthier heart; stronger bones National Osteoporosis Foundation (NOF) Feb 2008 Adults under age 50 need, per day 1,000 mg of calcium* 400-800 IU of vitamin D3 Adults 50 and over need, per day 1,200 mg of calcium* 800-1,000 IU of vitamin D3 * In divided doses, preferably with meals

Hot Flashes: Lifestyle Changes Exercise routinely, at least 3-4 days/week Cool room temperature, especially at night Dress in layers (remove outer layers if warm) Avoid hot and spicy foods Relaxing activities Avoid cigarettes Minimize alcohol A number of lifestyle and social factors may influence hot flush frequency: Warm ambient air temperatures increase a woman’s core body temperature and make her more likely to reach the sweating threshold Less physical activity increases the relative risk of hot flushes; daily exercise is associated with an overall decreased incidence Anecdotally, spicy foods have been reported to trigger hot flushes, though there is no clinical evidence to support this relationship Relaxation techniques may decrease or alleviate symptoms Other lifestyle factors that affect vasomotor symptoms: Cigarette smoking (past and current) increases the relative risk of hot flushes, perhaps because of its effect on estrogen metabolism While low levels of alcohol consumption (< or =1 drink per day for women) do not have a measurable effect on occurrence of vasomotor symptoms, greater amounts of alcohol intake may promote such symptoms. References North American Menopause Society. Menopause. 2004;11:11-33. Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-13. Huntley AL, Ernst E. Menopause. 2003;10:465-76. Greendale GA, Gold EB. Lifestyle factors: are they related to vasomotor symptoms and do they modify the effectiveness or side-effects of hormone therapy? Am J Med. 2005 Dec 19;118 Suppl 12B:148-54. North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10:465-76. North American Menopause Society. Menopause. 2004;11:11-33. Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-13. Huntley AL, Ernst E. Menopause. 2003;10:465-76.

Botanicals and PhytoSERMs Probably better than placebo Black cohosh No evidence of efficacy Soy isoflavones Not better than pbo Red clover isoflavones Not better than pbo Evening primrose oil Not better than pbo Dong quai Not better (as monotx) Ginseng Not better than pbo Vitamin E Not better than pbo Chasteberry (Vitex) No studies

Botanicals: Black Cohosh Total of 14 trials reported, including 4 randomized trials using placebo and/or estrogen treatment arm 3 of 4 RCTs found black cohosh to be beneficial 12 of 14 trials reported some benefit Currently, longest trial is 6 months NIH-funded, large, randomized, prospective, 2-year trial ongoing Preliminary data fail to show binding to E receptors Binding to serotonin receptor noted Four randomized trials of black cohosh with placebo or estrogen control groups have been conducted. Tablets (40mg/d) vs placebo; duration, 2 months1—Outcomes included frequency and intensity of hot flushes; menopause symptom index (6 symptoms); global rating of health scale; follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. FINDINGS: No significant difference between groups in frequency and intensity of hot flushes (decreased in both groups); significantly greater decrease in sweating in treatment group than in placebo group (P=.04); no changes in global rating scale or FSH and LH levels; study duration was short. Liquid (40 drops twice daily) vs conjugated estrogens (0.25mg/d) vs diazepam (2mg/d); duration, 3 months2—Outcomes included Kupperman index (KI) scores (modified 5 symptoms); Hamilton Anxiety scale (HAM-A); self-assessment depression scale (SDS); clinical global impression (CGI) scale; and vaginal maturation index (VMI). FINDINGS: Kupperman index, HAM-A, SDS, and CGI showed “highly significant reductions” with all three therapies; VMI: “trend toward estrogenic stimulation” for Remifemin and estrogen; no statistical calculations were reported. Tablets (4 mg twice daily) vs conjugated estrogens (0.625 mg/d) vs placebo; duration, 3 months3—Outcomes included Kupperman index scores (9 symptoms); hot flushes; HAM-A; VMI. FINDINGS: Significant improvement in Kupperman score, HAM-A (P=<.001), and VMI (P=<.01); no change in estrogen or placebo groups; hot flushes decreased from 4.9 to 0.7/d in Remifemin group, 5.2 to 3.2 in estrogen group, and 5.1 to 3.1 in placebo group (significance not indicated); lack of effect with estrogen calls other findings into question. Tablets (4 mg of triterpine glycosides twice daily) vs estriol (1 mg/d) vs conjugated estrogen (1.25 mg/d) vs estrogen/progesterone combination; duration, 6 months4—Outcomes included Kupperman index scores (modified 17 symptoms), LH and FSH levels. FINDINGS: Kupperman scores improved in all groups (P=.01); no differences among treatment groups; no changes in LH and FSH levels. Investigators note that there is a great need for alternatives to hormone therapy for use by symptomatic menopausal women. Alternatives to estrogen can encompass lifestyle change, complementary and alternative medicine (CAM), and prescription nonhormonal therapies. The use of CAM therapies for menopausal symptoms is widespread and has been increasing. A recent study indicates that relatively low concentrations of actein or the EtOAc fraction of black cohosh can cause synergistic inhibition of human breast cancer cell proliferation when combined with different classes of chemotherapy agents.   References 1Jacobson JS, et al. J Clin Oncol. 2001;19:2739-45. 2Warnecke G. Med Welt. 1985;36:871-4. 3Stoll W. Therapeutikon. 1987;1:23-31. 4Lehmann-Willenbrock E, Riedel HH. Zentralbl Gynakol. 1988;110:611-8. Kessel B, Kronenberg F. Endocrinol Metab Clin North Am. 2004 Dec;33(4):717-39. Einbond LS, et al. Planta Med. 2006 Oct;72(13):1200-6. Four randomized trials of black cohosh with placebo or estrogen control groups have been conducted. - Tablets (40 mg/d) vs placebo; duration, 2 months1—Outcomes included frequency and intensity of hot flushes; menopause symptom index (6 symptoms); global rating of health scale; follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. FINDINGS: No significant difference between groups in frequency and intensity of hot flushes (decreased in both groups); significantly greater decrease in sweating in treatment group than in placebo group (P = .04); no changes in global rating scale or FSH and LH levels; study duration was short. - Liquid (40 drops twice daily) vs conjugated estrogens (0.25 mg/d) vs diazepam (2 mg/d); duration, 3 months2—Outcomes included Kupperman index (KI) scores (modified 5 symptoms); Hamilton Anxiety scale (HAM-A); self-assessment depression scale (SDS); clinical global impression (CGI) scale; and vaginal maturation index (VMI). FINDINGS: Kupperman index, HAM-A, SDS, and CGI showed “highly significant reductions” with all three therapies; VMI: “trend toward estrogenic stimulation” for Remifemin and estrogen; no statistical calculations were reported. - Tablets (4 mg twice daily) vs conjugated estrogens (0.625 mg/d) vs placebo; duration, 3 months3—Outcomes included Kupperman index scores (9 symptoms); hot flushes; HAM-A; VMI. FINDINGS: Significant improvement in Kupperman score, HAM-A (P < .001), and VMI (P < .01); no change in estrogen or placebo groups; hot flushes decreased from 4.9 to 0.7/d in Remifemin group, 5.2 to 3.2 in estrogen group, and 5.1 to 3.1 in placebo group (significance not indicated); lack of effect with estrogen calls other findings into question - Tablets (4 mg of triterpene glycosides twice daily) vs estriol (1 mg/d) vs conjugated estrogens (1.25 mg/d) vs estrogen/progesterone combination; duration, 6 months4—Outcomes included Kupperman index scores (modified 17 symptoms), LH and FSH levels. FINDINGS: Kupperman scores improved in all groups (P = .01); no differences among treatment groups; no changes in LH and FSH levels. 1Jacobson JS, et al. J Clin Oncol. 2001;19:2739-45; 2Warnecke G. Med Welt. 1985;36:871-4. 3Stoll W. Therapeutikon. 1987;1:23-31. 4Lehmann-Willenbrock E, Riedel HH. Zentralbl Gynakol. 1988;110:611-8.

Botanicals: Black Cohosh Available as Remifemin, Estroven, or other single or combination products Dosage: 40-80 mg daily Adverse effects: headaches, stomach discomfort, heaviness in legs Hot Flashes

Non-hormonal Hot Flash Therapies Drug Hot Flash Reduction Antidepressants Paroxetine 62-65% Venlafaxine 38-60% Fluoxetine 20% Anticonvulsants Gabapentin 45% Antihypertensives Methyldopa 65% Clonidine 38% Menopause 2004; 11(1): 11-33 ACOG Task Force on HT Obstet Gynecol 2004; 104:106s-17s.

Therapeutic Interventions: Hormonal Medications Act 2 Therapeutic Interventions: Hormonal Medications

Prescription HT Options: ET and EPT Oral Transdermal Intravaginal ET Micronized estradiol Conjugated equine estrogens (CEE) Synthetic conjugated estrogens Esterified estrogens Estropipate Estradiol acetate Patches Gels Emulsion Spray Creams Intravaginal tablet Rings EPT CC-EPT CS-EPT E+P (combination) patches As you can see there are many different options and formulations for hormone therapy. Refer to your handout for more detailed information. Med Lett Drugs Ther 2004; 46:98. 39

HT Regimens Month 1 Month 2 Estrogen Progestin 14d Off for 14 d Continuous-sequential (CS) EPT Progestin Continuous combined (CC) EPT Estrogen Therapy (ET) 3d Continuous-pulsed (CP) EPT 40

Choice of HT Regimen If no uterus: estrogen only If uterus present Goal is to avoid vaginal bleeding entirely, or, at least, to make it predictable Endometrial activity predicts bleeding pattern Recent spontaneous or induced bleeding Continuous sequential No bleeding for >2-3 cycles Continuous combined 41

ET Oral Tablets Product Brand Standard dose Low dose Estropipate Ogen Ortho-est Generic 0.625 m none Micronized E2 Estrace 1.0 mg 0.5 mg Estradiol acetate Femtrace 0.9 mg 0.45 mg

ET Transdermal: Patch* Brand name Mg/24 hr Use/ wk Alora 0.025, 0.05, 0.075, 0.1 2 Esclim 0.025, 0.0375, 0.05, 0.075, 0.1 Estraderm 0.05, 0.1 Vivelle Vivelle-Dot Climara 0.025, 0.0375,0.05, 0.06, 0.075, 0.1 1 Menostar 0.014 ☼ * All contain 17B- estradiol only ☼ Indicated only for prevention of osteoporosis

ET Transdermal: Gels, Emulsions, Sprays* Brand name Type mg/24 hr Use Divigel Gel 0.25, 0.5, 1 mg/ packet 1 packet daily Elestrin 0.87 gm pump 1 pump daily EstroGel 1.25 gm pump Estrasorb Emulsion 1.74 gm/ pouch 2 pouches daily Evamist Spray 1.53 mg/ spray 1 spray daily * All contain 17B- estradiol only

Choice of Estrogens Start low dose transdermal or oral estrogen If suboptimal response, modify by: Change the estrogen dose (upward) Change the estrogen preparation Change delivery systems (oral transdermal) Consider an estrogen-androgen combination Injectable estrogen not recommended Dosage equivalencies are not known Estrogen cannot be discontinued easily

Route of Administration Non-oral routes of ET/EPT administration may offer advantages and disadvantages vs oral routes, but the long-term risk-benefit ratio has not been demonstrated Possible lower risk of deep venous thrombosis (DVT) with non-oral route Similar increased breast cancer risks with oral and transdermal estrogens, per large observational study NAMS position statement. Menopause 2007.

Oral vs. TD-E: The Risk of VTE The ESTHER Study OR = 4.0 (1.9-8.3) Adjusted Odds Ratio (95% CI) In the WHI, postmenopausal women randomly assigned to oral hormone therapy had 2.1 times higher risk of venous thromboembolic events than those receiving placebo. A large case-control study of postmenopausal women was conducted in order to explore the relationship between estrogen use and venous thromboembolism (VTE) risk. A total of 155 postmenopausal women with a first documented episode of idiopathic VTE were compared with 381 control women matched for age, study center, and time of recruitment. The case subjects included 92 women with pulmonary embolism and 63 women with deep vein thrombosis. After adjusting for potential confounding factors, women taking oral estrogen therapy had 3.5 times higher risk of VTE as compared with nonusers and 4.0 times higher risk as compared to those taking transdermal estrogen. Transdermal estrogen users did not have an increased risk of either DVT or PE. These results show that oral estrogen—but not transdermal estrogen—is associated with increased risk of VTE in postmenopausal women. Reference Scarabin P-Y, Oger E, Plu-Bureau G, et al. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428-432. Scarabin P-Y, et al. Lancet. 2003;362:428-432

“First Line” Use of Transdermal Estrogen Underlying medical conditions History of DVT or PTE High triglyceride levels Gall bladder disease Need for “steady state” drug release Daily mood swings (especially while on oral HT) Migraine headaches Inability to use oral tablets Stomach upset due to oral estrogen intake Problems with taking a daily pill

Lower HT Doses Provide nearly equivalent vasomotor and genital skin symptom relief and preservation of BMD compared to standard doses Additional local ET may be required for persistent vaginal symptoms Lower HT doses better tolerated and may have a better risk-benefit ratio than standard doses (cont’d) NAMS position statement. Menopause 2007.

Lower HT Doses (cont’d) Lower-than-standard ET/EPT doses should be considered, such as daily doses of 0.3 mg oral conjugated estrogens 0.25-0.5 mg oral micronized 17β-estradiol 0.025 mg transdermal 17β-estradiol patch or the equivalent NAMS position statement. Menopause 2007.

Progestogen Indication Primary menopause-related indication is endometrial protection from unopposed ET Adequate progestogen (as CC-EPT or CS-EPT) recommended with intact uterus Progestogen not generally indicated with ET post-hysterectomy NAMS position statement. Menopause 2007.

Progesterone/ Progestin Products Oral Progestin Equiv dose Available doses MPA 5-10 mg 1.2, 2.5, 5, 10 mg Micronized progesterone 200-300 mg 100, 200 mg Drospirenone 0.5 mg/d Norethindrone acetate 1.0 mg/d 0.5, 1.0 mg/d Norethindrone 0.7-1.0 mg/d 0.35 mg Norgestimate 0.09 mg Norgestrel 150 mcg/d

EPT Oral Tablets Estrogen Progestin Dosing Activella 17-E2 1 mg NETA 0.5 mg Once daily oral Angeliq Drosperinone 0.5 mg FemHRT EE 5 g EE 2.5 g NETA 1 mg NETA 0.5 mg Prefest 17- E2 1 mg Micronized NGM 0.09 mg E (alone) 3 days E+P 3 days Premphase 14 active 14 placebo CEE 0.625 mg MPA 5 mg (CS-EPT) Prempro 28 active CEE 0.625 mg 0.45 mg 0.3 mg MPA 5.0 mg; 2.5 mg 2.5 mg 1.5 mg (CC-EPT)

EPT Transdermal Patches Estrogen Progestin Dosing CombiPatch 17-E2 0.05 mg NETA 0.14 0.25 mg Twice weekly Climara Pro 17-E2 0.045 mg LNG 0.015 mg Once weekly

Off-Label EPT Uses Insufficient endometrial safety evidence to recommend off-label use of Long-cycle progestogen (ie, P every 3-6 months for 12-14 days) Vaginal administration of progesterone Levonorgestrel intrauterine system (Mirena) Low-dose estrogen without progestogen Close endometrial surveillance recommended with these approaches NAMS position statement. Menopause 2007.

Compounded Bioidentical Hormones “Then, suddenly, the Seven Dwarfs of Menopause arrived at my door without warning: Bitchy, Sweaty, Sleepy, Bloated, Forgetful, and All-Dried-Up….What was it that sent those wretched dwarfs packing? Natural bioidentical hormones.” Here we have Suzanne Sommers, who is largely responsible for bringing the concept of bioidenticals into the mainstream. Somers S. The Sexy Years: Discover the Hormone Connection: The Secret to Fabulous Sex, Great Health, and Vitality for Women and Men. Front Matter. 2004 Random House, Crown Publishing, NY.

Compounded Hormone Therapy The marketing of compounded hormonal therapy Only bioidentical hormones are used Combination of 2 or 3 estrogens is more “natural” Dosage is tailored to the individual More “pure” than commercial products Safer delivery systems (no dyes, etc) The reality The same hormones are used in commercial and compounded 17b-E2 and progesterone

Sources of Exogenous Hormones

Compounded Hormone Therapy Compounded hormones will probably work, but… Salivary hormone levels are not useful The value of adding E1 + E3 has not been evaluated Progesterone skin cream is not absorbed Compounded hormone doses are not standardized FDA-approved HT products will offer Bioidentical hormones Choice of delivery systems Formulary coverage/ lower out-of-pocket costs

http://www.fda.gov/consumer/updates/bioidenticals010908.pdf

Act 3 Practice Guidelines How can your patient use these treatments safely, effectively, and conveniently?

Treatment of Hot Flashes If mild sxs, try exercise, black cohosh + phytoSERM Initiate low dose HT if Moderate or severe symptoms Non-hormonal treatments have failed No interest in non-hormonal therapy Titrate estrogen dosage upward if needed When estrogen can’t be used, offer SSRI or SNRI Gabapentin, clonidine, a-methyldopa, MPA or Megesterol (Megace) Attempt discontinuation after 1-2 years 63

Treatment of Sleep/ Irritability Sxs If mild symptoms Lifestyle change, black cohosh, phytoSERMs If severe symptoms or no response to above Low dose HT, then titrate upward If mood swings, transdermal E preferred Depression component, or no response to HT SNRI or SSRI

HT and Vaginal Atrophy When HT is considered solely for this indication, local (not systemic) vaginal ET is generally recommended Progestogen generally not indicated with low-dose, local vaginal ET Vaginal lubricants often improve vaginal dryness and painful intercourse NAMS position statement. Menopause 2007.

Vaginal Estrogen Therapies Product Brand Dosage Dose Conjugated estrogen cream Premarin cream 0.625 mg/ gram Daily, then 1-3 time/wk Estradiol cream Estrace 0.01% (0.1 mg/ gm) Estradiol vaginal tablet Vagifem 25 micrograms Daily for 2 wks, BIW Estradiol ring Estring 7.5 mcg/ 24 hrs Every 90 days Estradiol ring* Femring 0.05 mg/d 0.1 mg/d Every 3 months *Intended to be used as systemic HT

Vaginal ET: Endometrial Surveillance? There are insufficient data to recommend annual endometrial surveillance in asymptomatic women using low-dose, local vaginal ET Closer surveillance may be required if a woman is At high risk for endometrial cancer Using a greater dose of vaginal ET Having symptoms such as spotting, breakthrough bleeding NAMS position statement. Menopause 2007.

HT and Cognition Initiating EPT after age 65 not recommended for primary prevention of dementia or cognitive decline Insufficient evidence to support ET/EPT for primary prevention of dementia when therapy is initiated during perimenopause or early postmenopause ET does not appear to convey direct benefit or harm for treatment of Alzheimer’s disease NAMS position statement. Menopause 2007.

HT and Cognition Many women experience worsening of short term memory with onset of menopause 9 RCTs and 8 cohort studies HT does not improve cognitive performance in women without symptoms If symptoms, HT improved verbal memory, reasoning, and motor speed tests Reasonable to provide HT to lessen cognitive changes in symptomatic menopausal women

Hormone Therapy and Fracture Prevention Pros Good data on fracture prevention (mainly 2o prevention) Relatively lower cost than boisphosphonates Less concern of adverse effects with ET alone (vs EPT) Cons Requires long term use and surveillance Post-menopausal bleeding can be troublesome Increased risk of breast cancer after 5 years of use Utility Fracture prophylaxis if using HT for another indication Otherwise, consider bisphosphonates as first line 70

HT and “Quality of Life” RCTs and retrospective studies show that HT has no effect on “quality of life” measures Many woman who wean from HT state that they “feel worse”…even after 20 years after menopause! Conventional wisdom In women who “feel better on/ worse off” of HT, continue low dose HT if few or no risk factors When (& how often) to re-attempt wean uncertain Don’t start HT for solely for improving QOL

Act 4 The Finale

Discontinuation of HT After 2 years, recommend a trial of HT discontinuation Is tapering from hormone therapy necessary? Grady D, Obstet Gynecol 2003;102:1233 n= 377 who attempted discontinuation of HT 74% successfully stopped; 26% resumed 71% stopped abruptly; 29% tapered: equal success “Rebound” hot flashes occur in some women and can last up to 3 months…many experts recommend a taper Taper hormone therapy over 8-12 weeks Reduce dose or extend intervals (every 2, then 3 days) Cut patches in half

If what I just said sounded unusually clear, then you must have misunderstood me Alan Greenspan