2. Starting and Stopping Hormone Therapy Marcelle I. Cedars, MD Director, Division of Reproductive Endocrinology University of California, San Francisco Women’s Health—Mount Zion San Francisco, California

3. “Yes” Most effective treatment strategy available for vasomotor symptoms Most effective treatment strategy available for vasomotor symptoms Known risks Known risks “No” Risks outweigh benefits No risk is acceptable Should Symptomatic Women Be Offered Hormone Therapy?

4. Approach Risk/Benefit Focus WHI Conclusion Population-based strategies Documentable “hard” disease, such as CVD, stroke, osteoporosis Global index of net harm 1 Patient-based care Individual risks (eg, family history, lifestyle) and patient symptoms and desires Absolute, attributable risk is small 1 CVD = cardiovascular disease; WHI = Women’s Health Initiative. Population Management vs Individual Care Concerns 1. [No Author]. JAMA. 2002;288:321.

5. Vasomotor Symptoms Common complaint Common complaint –Negatively impact quality of life –Typically abate within 2–3 years –Most clearly linked to hormonal changes Most common indication for initiation of hormone therapy Most common indication for initiation of hormone therapy

6. Additional Problems Associated with Menopause Vulvar and vaginal atrophy Vulvar and vaginal atrophy Postmenopausal osteoporosis Postmenopausal osteoporosis Sleeping difficulties Sleeping difficulties Alterations in mood (?) Alterations in mood (?) Alterations in cognition (?) Alterations in cognition (?)

7. Gold EB, et al. Am J Epidemiol. 2000;152:463. Vasomotor Symptoms Epidemiology Study of Women’s Health Across the Nation (SWAN) (2000) Study of Women’s Health Across the Nation (SWAN) (2000) –16,000+ women aged 40–55 years –>50% of late perimenopausal study patients experienced symptoms Impact of socioeconomic status, race/ethnicity, body mass index, smoking status, and physical activity Impact of socioeconomic status, race/ethnicity, body mass index, smoking status, and physical activity

8. Woods MF, et al. Am J Med. 2005;118:14. Vasomotor Symptoms Epidemiology Review of published longitudinal studies (2005) Review of published longitudinal studies (2005) –Prevalence throughout the transition Late reproductive stage, 6%–13% Late reproductive stage, 6%–13% Early to late menopausal stages, 4%–46% Early to late menopausal stages, 4%–46% Late menopausal transition, 33%–63% Late menopausal transition, 33%–63% Postmenopause, 79% Postmenopause, 79%

9. Vasomotor Symptoms When Is It Appropriate To Prescribe? Clinical decision-making = best available evidence + clinical judgment + patient education Clinical decision-making = best available evidence + clinical judgment + patient education –Balance between population statistics and individual patient fears and symptoms –>97% of women in WHI had no negative impact from hormone therapy 1 Most appropriate use with least controversy Most appropriate use with least controversy –Generally healthy women for short-term relief of intolerable menopausal symptoms –Lowest dose for shortest duration 1. NIH. WHI HT Update–2002. Available at: http://www.nhlbi.nih.gov/health/women/upd2002.htm.

10. Starting and Stopping Hormone Therapy The need The need –Symptomatic patients with few effective alternatives The problem The problem –Lack of high-quality data What to do? What to do? –The importance of individualization

11. Starting and Stopping Hormone Therapy Premature Ovarian Failure Early menopause a should not be accorded the same concerns as age-appropriate hormonal changes Early menopause a should not be accorded the same concerns as age-appropriate hormonal changes Limitation to 5 years (or any preset time frame) is artificial Limitation to 5 years (or any preset time frame) is artificial Benefits largely outweigh the risks Benefits largely outweigh the risks a Prior to 40 years of age.

12. Starting Hormone Therapy Late Reproductive Years/Early Transition Potential problems (still cycling) Potential problems (still cycling) –Abnormal bleeding (heavy, irregular) –Vasomotor symptoms –Vaginal dryness –Increasing “PMS” PMS = premenstrual syndrome.

13. Route of administration Route of administration –? impact on specific symptoms –Mood and headache may benefit from transdermal (continuous dosing) Dosing Dosing –Additional goal of suppressing endogenous cycles and mimic of circulating levels –Transverse menstrual cycle mean: approximately 100 pg/mL Cyclic vs continuous Cyclic vs continuous –Side-effect profile in cycling women with combined continuous dosing Starting Hormone Therapy Late Reproductive Years/Early Transition

14. Starting Hormone Therapy Mid-to-Late Transition Through Postmenopause Problems (largely not cycling) Problems (largely not cycling) –Vasomotor symptoms –Vaginal dryness –Urinary symptoms

15. Route of administration Route of administration –Patient preference –Mood and headache may benefit from transdermal (continuous dosing) –Vulvo-vaginal symptoms – importance of local Dosing Dosing –Lowest effective dose Cyclic vs continuous Cyclic vs continuous –Patient preference for cycles –Information regarding higher breast cancer risk with continuous progestin 1 –Alternative progestin dosing/route of administration Starting Hormone Therapy Mid-to-Late Transition Through Postmenopause 1. Heiss G, et al. JAMA. 2008;299:1036.

16. Stopping Hormone Therapy Stopping (by choice) after 12 months of starting Stopping (by choice) after 12 months of starting –62% older women (≥65 years) –48% younger women (50–55 years) –Reason: vaginal bleeding Ettinger B, et al. Menopause. 1999;6:282.

17. Grady D, et al. Obstet Gynecol. 2003;102:1233. Telephone interviews of Kaiser population Telephone interviews of Kaiser population –Women aged 50–69 years who took hormone therapy ≥1 year (N = 377) 74% successfully stopped 74% successfully stopped 26% resumed treatment 26% resumed treatment –Troublesome withdrawal symptoms –Hysterectomy –Hormone therapy from a nongynecologist –Perceived higher risk for fracture Stopping Hormone Therapy Predictors of Difficulty Stopping

18. Symptoms after stopping hormone therapy in Kaiser-population study Symptoms after stopping hormone therapy in Kaiser-population study –70% reported no/minimal symptoms –30% reported troublesome symptoms 62% of women unable to stop treatment 62% of women unable to stop treatment 19% of those who successfully quit 19% of those who successfully quit Stopping Hormone Therapy Withdrawal Symptoms Grady D, et al. Obstet Gynecol. 2003;102:1233.

19. Telephone interview of community sample Telephone interview of community sample –533 women aged 45–54 years (N = 533) Factors related to discontinuation of hormone therapy Factors related to discontinuation of hormone therapy –Increased understanding of risks/benefits –Confidence –Mental health symptoms –History of gynecologic surgery –Perception that menopause is natural Stopping Hormone Therapy Likelihood of Discontinuation Bosworth HB, et al. J Behav Med. 2005;28:105.

20. Haimov-Kochman R, et al. Menopause. 2006;13:370. Stopping Hormone Therapy Taper vs Abrupt Cessation Randomized controlled trial (N = 91) Randomized controlled trial (N = 91) Reappearance of vasomotor symptoms Reappearance of vasomotor symptoms –<3 months after discontinuing therapy Less-severe symptoms with taper cessation Less-severe symptoms with taper cessation –At 6 months Less-severe symptoms with abrupt cessation Less-severe symptoms with abrupt cessation –At 9–12 months No difference in symptoms between taper or abrupt cessation No difference in symptoms between taper or abrupt cessation Similar percentage in each group resumed treatment Similar percentage in each group resumed treatment

21. Taper vs abrupt cessation may not affect recurrence of symptoms 1 Taper vs abrupt cessation may not affect recurrence of symptoms 1 Taper may allow titration to lowest effective dosing 2 Taper may allow titration to lowest effective dosing 2 Taper may allow individualized slow, long taper (hold at dose where symptoms recur then attempt taper again after stabilized) 3 Taper may allow individualized slow, long taper (hold at dose where symptoms recur then attempt taper again after stabilized) 3 Stopping Hormone Therapy Taper vs Abrupt Cessation 1. Aslan E, et al. Maturitas. 2007;56:78. 2. Haimov-Kochman R, et al. Menopause. 2006;13:370. 3. Grady D. Menopause. 2006;13:323.

22. Conclusions Individualization is important Individualization is important Quality of life issues are important but should be weighed against an individual patient’s health risk 1 Quality of life issues are important but should be weighed against an individual patient’s health risk 1 –Risks are small, but when an event occurs, impact on personal QALE is significant –Severity of symptoms weighed against CVD risk Continued treatment should be reviewed annually Continued treatment should be reviewed annually 1. Col NF, et al. Arch Intern Med. 1004;164:1634. QALE = quality-adjusted life expectancy; CVD = cardiovascular disease.

23. Brief Q & A