Transcript Document
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
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Micronized progesterone
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Progestin intrauterine device
Vaginal estrogen
Bioidentical hormones
Estrogen Dose Equivalents
Estrogen Standard CEE Oral E2 Transdermal E2 0.625 mg 1 mg 0.05 mg (50 µg) Ethinyl estradiol 5 µg
CEE = conjugated equine estrogen; E2 = estradiol.
Graphic courtesy of Kathryn A. Martin, MD.
Low Dose 0.3 mg 0.5 mg 0.025 mg (25 µg) 2.5 µg Ultra-Low Dose 0.014 mg (14 µg)
Low-Dose Estrogen
HOPE 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.
CEE and Hot Flashes
HOPE Trial
100 80 60 Placebo 40 20 0 0 4 8 Week
Adapted from Utian WH, et al.
Fertil Steril
. 2001;75:1065, with permission from Elsevier.
CEE 0.45 mg/d CEE 0.3 mg/d CEE 0.625 mg/d 12
Ultra –Low-Dose Estrogen
ULTRA trial: Ultra –low-dose Transdermal Estradiol Assessment 1
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Transdermal E2 (0.014 mg/day) vs placebo x 2 years
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N = 417 women, mean age 67 Asymptomatic population – no effect on hot flashes 2
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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0 -1 -2 -3 3 2 1 0
CEE and Spine BMD
HOPE Trial
6 12 18 24 Month Placebo CEE 0.3 mg CEE 0.45 mg CEE 0.625 mg
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.
Ultra –Low-Dose Estrogen and BMD
ULTRA Trial
BMD increased more in spine (2%) and hip (1.2%) vs placebo 1
Greater bone effect with lower endogenous E 2
1. Ettinger B, et al.
Obstet Gynecol.
2004;104:443. 2. Huang AJ, et al.
J Bone Miner Res.
2007;22:1791.
Endometrial Effects of Lower Doses of Estrogens
HOPE trial
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Similar endometrial protection with lower doses + MPA compared with commonly prescribed doses 1
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Less vaginal bleeding with low dose 2
ULTRA trial
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No increased uterine bleeding or hyperplasia compared with placebo 3
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Endometrial proliferation 8.5% vs 1.1% with placebo (NS) 3
Ability to use lower-dose progestins, but no consensus on correct progestin dosing 4
1. Pickar JH, et al.
Fertil Steril.
3. Archer DF, et al.
Fertil Steril.
2001;76:25. 2. Johnson SR, et al.
Obstet Gynecol.
2001;75:1080. 4. Ettinger B.
Am J Med.
2005;105:779. 2005;118:74.
Lipids
Safety Profile of Lower Doses of Estrogen
Increased HDL, decreased LDL (HOPE trial) 1 Stroke VTE Breast Vaginal symptoms Low dose protective, standard dose increased risk (Nurses’ Health Study) 2 Risk appears to be lower compared with standard dose 3 No increase in breast density vs placebo (ULTRA trial) 4 ; breast cancer risk unknown Increased vaginal discharge only (ULTRA trial for both) 5 ; less vaginal bleeding 6
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.
Transdermal Estrogen
Estrogen and Thromboembolism Risk (ESTHER) study 1
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Case-control study (271 cases, 610 controls) Lower risk of VTE compared with oral E2 (OR 4.2) Markers of inflammation unaffected 2 ; triglycerides decreased 3 ; less effect on SHBG and TBG 2 Less favorable for HDL and LDL changes 4 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.
Other
Estrogen Preparations
Topical estrogen
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Estradiol gel: non-aerosol, metered-dose pump applied once daily (0.75 mg/1.25 g) on one arm 1
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Estradiol topical emulsion: white lotion-like emulsion applied once daily (0.05 mg/2 pouches) 2
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Low-dose preps: gels 3,4 and 1 topical spray 5 Vaginal ring
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Delivers estradiol 0.05 or 0.10 mg/d 6
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.
Progestins —Micronized Progesterone
Micronized progesterone vs medroxyprogesterone
Metabolic —does not negate beneficial effect of estrogen on lipids 1
Breast cancer: less risk with progesterone than synthetic progestins 2
Sleep: differential effects on sleep 3
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.
Progestins —Levonorgestrel Intrauterine Device
Delivers 20 µg/day for 5 years 1 Local effects on endometrium with minimal systemic effects 1 ; prevents hyperplasia 2 Approved for contraception 1 (and for hormone therapy in some countries)
Majority develop amenorrhea, but issues with breakthrough bleeding in some 3
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.
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
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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.
Vaginal Estrogen
Genitourinary atrophy symptoms
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Vaginal dryness, painful intercourse, urinary symptoms
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50% in late menopause 1 ; if untreated, symptoms persist or worsen 2
Vaginal estrogen
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Greater potency than systemic estrogen 3 With low doses: minimal systemic absorption 4
1. Notelovitz M.
Int J Gynaecol Obstet.
3. Cardozo L, et al.
Obstet Gynecol.
1997;59 (suppl 1):S35. 2. Woods NF, et al. 1998;92:722. 4. Weisberg E, et al.
Climacteric.
Am J Med.
2005;8:83.
2005;118 (suppl 12B):14.
Vaginal Estrogen —Standard Dose
Dose: 0.5
–4 g (1/4 to full applicator) 1,2
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1 g CEE cream = 0.625 mg CEE 1
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1 g E2 cream = 100 µg E2 2
Standard doses may increase serum estrogen concentrations, suppress LH, FSH 3,4
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.
Vaginal Estrogen —Low Dose
Options
– –
Vaginal estradiol tablets: 10 µg and 25 µg 1 Vaginal ring
No significant endometrial thickening 2
Serum estradiol concentrations
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25 µg dose
20 pg/mL 3 10 µg dose
<10 pg/mL 4
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.
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
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FDA actions