Cases in Menopause

When should a menopausal woman discontinue hormone therapy?

OBG Manag. 2014 February;26(2):59-65

	Andrew M. Kaunitz, MD Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. Dr. Kaunitz is a NAMS Board member and certified menopause practitioner. He also serves on the OBG Management Board of Editors.
	JoAnn V. Pinkerton, MD Professor, Department of Obstetrics and Gynecology, and Director, Division of Midlife Women’s Health, University of Virginia. Dr. Pinkerton is a North American Menopause Society (NAMS) past president and certified menopause practitioner. She also serves on the OBG Management Board of Editors.
	James A. Simon, MD Clinical Professor, Department of Obstetrics and Gynecology, George Washington University, and Medical Director, Women’s Health & Research Consultants, Washington, DC. Dr. Simon is a NAMS past president, a certified menopause practitioner, and a certified clinical densitometrist. He also serves on the OBG Management Board of Editors.

References

Kaunitz AM. NAMS Practice Pearl: Extended duration use of menopausal hormone therapy [published online ahead of print January 6, 2014]. Menopause.
North American Menopause Society. Position Statement: The 2012 hormone therapy position statement of the North American Menopause Society. Menopause. 2012;19(3):257–271.
Nelson HD. Postmenopausal estrogen for treatment of hot flashes: clinical applications. JAMA. 2004;291(13):1621–1625.
Hulley SB, Grady D. The WHI estrogen-alone trial—do things look any better? JAMA. 2004;291(14):1769–1771.
Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol. 2011;117(5):1095–1104.
Huang AJ, Grady D, Jacoby VL, Blackwell TL, Bauer DC, Sawaya GF. Persistent hot flushes in older postmenopausal women. Arch Intern Med. 2008;168(8):840–846.
Ettinger B, Ensrud KE, Wallace R, Johnson KC, Cummings SR, Yankov V, Vittinghoff E, Grady D. Effects of ultralow-dose transdermal estradiol on bone mineral density: A randomized clinical trial. Obstet Gynecol. 2004;104(3):443–451.
Johnson SR, Ettinger B, Macer JL, Ensrud KE, Quan J, Grady D. Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol. Obstet Gynecol. 2005;105(4):779–787.
Menostar [package insert]. Wayne, NJ: Bayer; 2007.
Diem S, Grady D, Quan J, Vittinghoff E, Wallace R, Hanes V, Ensrud K. Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years. Menopause. 2006;13(1):130–138.
Bachmann GA, Schaefers M, Uddin A, Utian WH. Lowest effective transdermal 17beta-estradiol dose for relief of hot flushes in postmenopausal women: A randomized controlled trial. Obstet Gynecol. 2007;110(4):771–779.
Honjo H, Taketani Y. Low-dose estradiol for climacteric symptoms in Japanese women: A randomized, controlled trial. Climacteric. 2009;12(4):319–328.
Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;75(6):1065–1079.
Premarin [package insert]. Philadelphia, PA: Pfizer; 2012.
American College of Obstetricians and Gynecologists. Practice Bulletin No. 141: Management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202–216.
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.
Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.
Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;4:297(13):1465–1477.
Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol. 2010;30(2):340–345.
Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. 2012. doi:10.1111/j.1538-7836.2012.04919.x.
Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.
Renoux C, Dell’Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: A population-based study. J Thromb Haemost. 2010;8(5):979–986.
Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause. 2011;18(10):1052–1059.
Scarabin PY, Oger E, Plu-Bureau G; EStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362(9382):428–432.
Renoux C, Dell’Aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: A nested case-control study. BMJ. 2010;340:c2519. doi:10.1136/bmj.c2519.
American College of Obstetricians and Gynecologists. Committee Opinion No. 556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.
Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;14(1):25–31.
North American Menopause Society. 2013 Position Statement: Management of symptomatic vulvovaginal atrophy. Menopause. 2013;20(9):888–902.
Nelken RS, Ozel BZ, Leegant AR, Felix JC, Mishell DR. Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder. Menopause. 2011;18(9):962–966.
Eriksen BC. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180(5):1072–1079.
North American Menopause Society. 2010 Position Statement: Management of osteoporosis in postmenopausal women. Menopause. 2010;17(1):25–54.

At age 61, because of her maternal history of osteoporosis and her own low BMI, the patient undergoes BMD assessment with dual x-ray absorptiometry (DXA). In average-risk women, NAMS recommends that BMD assessment be performed at age 65.³¹ The results of BMD assessment are normal.

After further discussion, the patient agrees to an even lower dose of estradiol, switching to an 0.025-mg patch, with progesterone (100 mg nightly) administered for 2 weeks in every 3-month interval. She reports no VMS or vaginal bleeding on this lower-dose HT regimen.

After 12 months on this new regimen, the patient undergoes vaginal sonography, revealing an endometrial thickness of 3 mm. She continues this regimen, including annual vaginal ultrasound assessment of the endometrium, without problems until her well-woman visit at age 65.

At that visit, I explain that discontinuation of HT is unlikely to trigger recurred VMS but may cause her to lose BMD rapidly for several years, and may also result in unpleasant symptoms from vulvovaginal atrophy including sexual discomfort. She decides to switch to an 0.014-mg estradiol patch without progesterone, and to undergo ultrasound assessment of her endometrium every 1 to 2 years.

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BOTTOM LINE: INDIVIDUALIZE THE DURATION OF HT
Although published data on extended use of HT are few, many clinicians caring for menopausal women are asked to make a recommendation. Because extended use of estrogen-progestin HT increases the risk of breast cancer, estrogen-only HT has a more favorable benefit-risk ratio. If a patient uses estrogen-progestin HT for an extended duration, periodic discussions about the elevated risk of breast cancer are appropriate.

JoAnn V. Pinkerton, MD:
The risk of breast cancer associated with extended use of estrogen-progestin HT likely is reduced if lower doses are given. Overall, however, the risk appears to be both dose- and duration-dependent.

We lack randomized trial data on CHD and other risks in women who begin HT at the time of menopause and continue it for decades. In older women who use HT for an extended duration, transdermal estrogen may be safer in regard to the risk of VTE and stroke.

As the systemic estrogen dose is lowered, it is possible to reduce the dose of the progestin (the sole function of which is to protect the endometrium from estrogen stimulation). Intermittent dosing can be used, although we lack long-term safety data, and periodic endometrial evaluation should be considered.

Remember also that, with intermittent or daily dosing of a progestin, you are relying on the patient to take this medication to protect the endometrium.

Extended use of low-dose vaginal estrogen HT may be necessary to treat symptoms of vulvovaginal atrophy, which tend to worsen over time. Administration of a progestin is not currently recommended with use of vaginal estrogen, but long-term use may increase the risk of endometrial stimulation.

Read other CASES IN MENOPAUSE
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References

Kaunitz AM. NAMS Practice Pearl: Extended duration use of menopausal hormone therapy [published online ahead of print January 6, 2014]. Menopause.
North American Menopause Society. Position Statement: The 2012 hormone therapy position statement of the North American Menopause Society. Menopause. 2012;19(3):257–271.
Nelson HD. Postmenopausal estrogen for treatment of hot flashes: clinical applications. JAMA. 2004;291(13):1621–1625.
Hulley SB, Grady D. The WHI estrogen-alone trial—do things look any better? JAMA. 2004;291(14):1769–1771.
Freeman EW, Sammel MD, Lin H, Liu Z, Gracia CR. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol. 2011;117(5):1095–1104.
Huang AJ, Grady D, Jacoby VL, Blackwell TL, Bauer DC, Sawaya GF. Persistent hot flushes in older postmenopausal women. Arch Intern Med. 2008;168(8):840–846.
Ettinger B, Ensrud KE, Wallace R, Johnson KC, Cummings SR, Yankov V, Vittinghoff E, Grady D. Effects of ultralow-dose transdermal estradiol on bone mineral density: A randomized clinical trial. Obstet Gynecol. 2004;104(3):443–451.
Johnson SR, Ettinger B, Macer JL, Ensrud KE, Quan J, Grady D. Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol. Obstet Gynecol. 2005;105(4):779–787.
Menostar [package insert]. Wayne, NJ: Bayer; 2007.
Diem S, Grady D, Quan J, Vittinghoff E, Wallace R, Hanes V, Ensrud K. Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years. Menopause. 2006;13(1):130–138.
Bachmann GA, Schaefers M, Uddin A, Utian WH. Lowest effective transdermal 17beta-estradiol dose for relief of hot flushes in postmenopausal women: A randomized controlled trial. Obstet Gynecol. 2007;110(4):771–779.
Honjo H, Taketani Y. Low-dose estradiol for climacteric symptoms in Japanese women: A randomized, controlled trial. Climacteric. 2009;12(4):319–328.
Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;75(6):1065–1079.
Premarin [package insert]. Philadelphia, PA: Pfizer; 2012.
American College of Obstetricians and Gynecologists. Practice Bulletin No. 141: Management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202–216.
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.
Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.
Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;4:297(13):1465–1477.
Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol. 2010;30(2):340–345.
Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. 2012. doi:10.1111/j.1538-7836.2012.04919.x.
Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.
Renoux C, Dell’Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: A population-based study. J Thromb Haemost. 2010;8(5):979–986.
Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause. 2011;18(10):1052–1059.
Scarabin PY, Oger E, Plu-Bureau G; EStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362(9382):428–432.
Renoux C, Dell’Aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: A nested case-control study. BMJ. 2010;340:c2519. doi:10.1136/bmj.c2519.
American College of Obstetricians and Gynecologists. Committee Opinion No. 556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.
Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;14(1):25–31.
North American Menopause Society. 2013 Position Statement: Management of symptomatic vulvovaginal atrophy. Menopause. 2013;20(9):888–902.
Nelken RS, Ozel BZ, Leegant AR, Felix JC, Mishell DR. Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder. Menopause. 2011;18(9):962–966.
Eriksen BC. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol. 1999;180(5):1072–1079.
North American Menopause Society. 2010 Position Statement: Management of osteoporosis in postmenopausal women. Menopause. 2010;17(1):25–54.

When should a menopausal woman discontinue hormone therapy?

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