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Efficacy and Safety Profiles of New and Emerging Menopause Treatments

Efficacy and Safety Profiles of New and Emerging Menopause Treatments. Kathryn A. Martin, MD Reproductive Endocrine Unit Massachusetts General Hospital Boston, Massachusetts. Hormone Products. Estrogen Low doses Alternate routes of administration Progestins Micronized progesterone

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Efficacy and Safety Profiles of New and Emerging Menopause Treatments

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  1. Efficacy and Safety Profiles of New and Emerging Menopause Treatments Kathryn A. Martin, MD Reproductive Endocrine UnitMassachusetts General Hospital Boston, Massachusetts

  2. Hormone Products • Estrogen • Low doses • Alternate routes of administration • Progestins • Micronized progesterone • Progestin intrauterine device • Vaginal estrogen • Bioidentical hormones

  3. Estrogen Dose Equivalents CEE = conjugated equine estrogen; E2 = estradiol.Graphic courtesy of Kathryn A. Martin, MD.

  4. Low-Dose EstrogenHOPE Trial • Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial • 2600+ postmenopausal women with uterus,treated for 2 years • 8 treatment groups and placebo • CEE 0.625 mg/d ± MPA 2.5 mg/d • CEE 0.45 mg/d ± MPA 2.5 mg/d • CEE 0.45 mg/d + MPA 1.5 mg/d • CEE 0.3 mg/d ± MPA 1.5 mg/d • Placebo • Endpoints: vasomotor symptoms,BMD,endometrial safety CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate; BMD = bone mineral density.Utian WH, et al. Fertil Steril. 2001;75:1065.

  5. CEE and Hot FlashesHOPE Trial Placebo CEE 0.45 mg/d CEE 0.3 mg/d CEE 0.625 mg/d Adapted from Utian WH, et al. Fertil Steril. 2001;75:1065, with permission from Elsevier.

  6. Ultra–Low-Dose Estrogen • ULTRA trial: Ultra–low-dose Transdermal Estradiol Assessment1 • Transdermal E2 (0.014 mg/day) vs placebo x 2 years • N = 417 women, mean age 67 • Asymptomatic population – no effect on hot flashes2 • Effective for hot flashes in trials of younger women (N = 425)3 1. Yaffe K, et al. Arch Neurol. 2006;63:945. 2. Diem S, et al. Menopause. 2006;13:130. 3. Bachmann GA, et al. Obstet Gynecol. 2007;110:771.

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  8. CEE and Spine BMDHOPE Trial 3 2 1 Placebo CEE 0.3 mg Change Spine BMD (%) 0 CEE 0.45 mg 0 6 12 18 24 CEE 0.625 mg -1 -2 -3 Month CEE = conjugated equine estrogen; BMD = bone mineral density.Reprinted from Lindsay R, et al. JAMA. 2002;287:2668, with permission from the American Medical Association.

  9. Ultra–Low-Dose Estrogen and BMDULTRA Trial • BMD increased more in spine (2%)and hip (1.2%) vs placebo1 • Greater bone effect with lowerendogenous E2 1. Ettinger B, et al. Obstet Gynecol. 2004;104:443. 2. Huang AJ, et al. J Bone Miner Res. 2007;22:1791.

  10. Endometrial Effects of Lower Dosesof Estrogens • HOPE trial • Similar endometrial protection with lower doses + MPA compared with commonly prescribed doses1 • Less vaginal bleeding with low dose2 • ULTRA trial • No increased uterine bleeding or hyperplasia compared with placebo3 • Endometrial proliferation 8.5% vs 1.1% with placebo (NS)3 • Ability to use lower-dose progestins, but no consensus on correct progestin dosing4 1. Pickar JH, et al. Fertil Steril. 2001;76:25. 2. Johnson SR, et al. Obstet Gynecol. 2005;105:779. 3. Archer DF, et al. Fertil Steril. 2001;75:1080. 4. Ettinger B. Am J Med. 2005;118:74.

  11. Safety Profile of Lower Doses of Estrogen HDL = high-density lipoprotein; LDL = low-density lipoprotein; VTE = venous thromboembolism. 1. Lobo RA, et al. Fertil Steril. 2001;76:13. 2. Grodstein F, et al. Ann Intern Med. 2000;133:933. 3. Jick H, et al. Lancet. 1996;348:981. 4. Grady D, et al. Menopause. 2007;14:391. 5. Diem S, et al. Menopause. 2006;13:130. 6. Archer DF,et al. Fertil Steril. 2001;75:1080.

  12. Transdermal Estrogen • Estrogen and Thromboembolism Risk (ESTHER) study1 • Case-control study (271 cases, 610 controls) • Lower risk of VTE compared with oral E2 (OR 4.2) • Markers of inflammation unaffected2;triglycerides decreased3;less effect on SHBG and TBG2 • Less favorable for HDL and LDL changes4 • Patient preference important (transdermal vs oral) • Wide range of dosing options (mg/d): 0.014, 0.025, 0.0375, 0.05, 0.075, 0.1 SHBG = sex hormone-binding globulin; TBG = thyroxine-binding globulin. 1. Canonico M, et al. Circulation. 2007;115:840. 2. Shifren JL, et al. Endocrinol Metab. 2008;93:1702. 3. Sanada M, et al. Menopause. 2004;11:331. 4. Walsh BW, et al. N Engl J Med. 1991;325:1196.

  13. Other Estrogen Preparations • Topical estrogen • Estradiol gel: non-aerosol, metered-dose pump applied once daily (0.75 mg/1.25 g) on one arm1 • Estradiol topical emulsion: white lotion-like emulsion applied once daily (0.05 mg/2 pouches)2 • Low-dose preps: gels3,4 and 1 topical spray5 • Vaginal ring • Delivers estradiol 0.05 or 0.10 mg/d6 1. EstroGel 0.06% (estradiol gel). Prescribing information(PI). Montrouge, France: ASCEND Therapeutics, 2007. 2. Estrosorb (estradiol topical emulsion). PI. Bristol, TN: Graceway Pharmaceuticals, LLC, 2008. 3. Divigel 0.1% (estradiol gel). PI. Minneapolis, MN: Upsher-Smith Laboratories, Inc., 2007. 4. Elestrin (estradiol gel). PI. Fairfield, NJ: Kenwood Therapeutics, 2007. 5. Evamist (estradiol transdermal spray). PI. St. Louis, MO: Ther-Rx Corporation, 2008. 6. Femring (estradiol acetate vaginal ring). PI. Rockaway, NJ: Warner Chilcott, 2008.

  14. Progestins—Micronized Progesterone • Micronized progesterone vs medroxyprogesterone • Metabolic—does not negate beneficialeffect of estrogen on lipids1 • Breast cancer: less risk with progesterone than synthetic progestins2 • Sleep: differential effects on sleep3 1. [No Author.] JAMA. 1995;273:199. 2. Fournier A, et al. Breast Cancer Res Treat. 2008;107:103. 3. Montplaisir J, et al. Menopause. 2001;8:10.

  15. Progestins—Levonorgestrel Intrauterine Device • Delivers 20 µg/day for 5 years1 • Local effects on endometrium with minimal systemic effects1; prevents hyperplasia2 • Approved for contraception1 (and for hormone therapy in some countries) • Majority develop amenorrhea, but issues with breakthrough bleeding in some3 • No evidence of breast cancer risk (but younger populations studied)4 1. Mirena (levonorgestrel-releasing intrauterine system). Prescribing information. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc., 2007. 2. Wildemeersch D, et al. Maturitas. 2007;57:205. 3. Suvanto-Luukkonen E, et al. Fertil Steril. 1999;72:161. 4. Backman T, et al. Obstet Gynecol. 2005;106:813.

  16. Combination Products • Oral preparations • CEE (0.3–0.625 mg) + MPA (1.5–5 mg)1 • E2 (1 mg) + norgestimate (0.9 mg)2 • E2 (1 mg) + norethindrone acetate (0.5 mg)3 • E2 (1 mg)+ drospirenone (0.5 mg)4 • CEE (0.625 mg/1.25 mg) + methyltestosterone (1.25 mg/2.5 mg)5 • Transdermals • E2 0.05 mg + norethindrone acetate (0.14–0.25 mg)6 • E2 0.05 mg + levonorgestrel (0.015 mg)7 1. PREMPRO/PREMPHASE (conjugated estrogens/medroxyprogesterone acetate tablets). Prescribing information(PI). Philadelphia, PA: Wyeth Pharmaceuticals Inc., 2006. 2. PREFEST (estradiol/norgestimate) Tablets. PI. Bristol, TN: Monarch Pharmaceuticals, 2000. 3. Activella (estradiol/norethindrone acetate) Tablets. PI. Princeton, NJ: Novo Nordisk Inc., 2006. 4. Angeliq Tablets (drospirenone/estradiol). PI. Montville, NJ: Berlex, 2005. 5. Estratest (esterified estrogens and methyltestosterone) Tablets. PI. Marietta, GA: Solvay Pharmaceuticals, Inc., 2005. 6. CombiPatch (estradiol/norethindrone acetate transdermal system). PI. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2005. 7. Climara Pro (estradiol/levonorgestrel transdermal system). PI. Montville, NJ: Berlex, 2003.

  17. Vaginal Estrogen • Genitourinary atrophy symptoms • Vaginal dryness, painful intercourse, urinary symptoms • 50% in late menopause1; if untreated, symptoms persist or worsen2 • Vaginal estrogen • Greater potency than systemic estrogen3 • With low doses: minimal systemic absorption4 1. Notelovitz M. Int J Gynaecol Obstet. 1997;59 (suppl 1):S35. 2. Woods NF, et al. Am J Med. 2005;118 (suppl 12B):14.3. Cardozo L, et al. Obstet Gynecol. 1998;92:722. 4. Weisberg E, et al. Climacteric. 2005;8:83.

  18. Vaginal Estrogen—Standard Dose • Dose: 0.5–4 g (1/4 to full applicator)1,2 • 1 g CEE cream = 0.625 mg CEE1 • 1 g E2 cream = 100 µg E22 • Standard doses may increase serum estrogen concentrations, suppress LH, FSH3,4 • Endometrial proliferation in some studies, but progestin not routinely recommended (NAMS)4 LH = luteinizing hormone; FSH = follicle-stimulating hormone; NAMS = North American Menopause Society. 1. Premarin (conjugated estrogens). Prescribing information. Philadelphia, PA: Wyeth Pharmaceuticals Inc, 2008.2. Estrace Cream (estradiol vaginal cream). Prescribing information. Rockaway, NJ: Warner Chilcott (US), Inc, 2007.3. Rioux JE, et al. Menopause. 2000;7:156. 4. North American Menopause Society. Menopause. 2007; 14:357.

  19. Vaginal Estrogen—Low Dose • Options • Vaginal estradiol tablets: 10 µg and 25 µg1 • Vaginal ring • No significant endometrial thickening2 • Serum estradiol concentrations • 25 µg dose  20 pg/mL3 • 10 µg dose  <10 pg/mL4 1. Bachmann G, et al. Obstet Gynecol. 2008;111:67. 2. Rioux JE, et al. Menopause. 2000;7:156.3. Notelovitz M, et al. Obstet Gynecol. 2002;99:556. 4. Santen RJ, et al. Menopause. 2002;9:179.

  20. Bioidentical Hormones • “Bioidentical” or “natural” hormones • Term refers to individualized preparations of steroid hormones (estrogen/estriol, progesterone, or testosterone) compounded as creams, gels, pills, or suppositories • Baseline saliva or blood tests for “customization” • Lack of quality control; lack of efficacy/safety data • FDA actions

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