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.

Similarly, one observational study suggests that low-dose (≤0.05 mg) transdermal estradiol does not appear to increase the risk of stroke,²⁵ but, again, clinical trial data are unavailable.

Given these apparent safety advantages, transdermal estrogen therapy would appear to be preferable to oral estrogen in older, long-term users, a perspective supported by ACOG.²⁶

Related Article: Is one oral estrogen formulation safer than another for menopausal women? Andrew M. Kaunitz, MD (Examining the Evidence, January 2014)

In regard to VTE, oral estradiol appears to be safer than CEE.²⁷ Accordingly, oral estradiol may be preferable for older long-term users who don’t tolerate transdermal estradiol due to local skin reactions or costs. Oral estradiol also is less expensive than CEE.

What to expect when your patient discontinues systemic HT
VMS may recur is as many as 50% of women after they discontinue HT. The likelihood of recurring VMS does not appear to vary between abrupt and tapered discontinuation.²

Some HT users may be reluctant to reduce their dose or discontinue HT, particularly those who experienced severe VMS originally. In my clinical experience, many of these women are receptive to a trial of lower-dose HT, especially when I advise them that they can resume their original (higher) dose should bothersome VMS recur.

JoAnn V. Pinkerton, MD:
I use a similar approach with my patients, advising them to try 3 months off HT with the understanding that they can resume the therapy if they develop bothersome symptoms.

Individualized assessment of HT benefits and risks and shared decision-making play important roles in the management of these patients. As the dose of HT declines, or systemic HT is discontinued, symptoms of genital atrophy may become more prominent and, in the absence of indications for systemic HT (bothersome VMS or prevention of osteoporosis), may best be addressed with vaginal estrogen therapy or ospemifene.

Extended use of vaginal estrogen
Unlike VMS, untreated genital atrophy may continue to progress as women age, sometimes necessitating use of vaginal estrogen. Because the clinical trials that served as the basis for FDA approval of vaginal estrogen formulations did not find an elevated risk of endometrial hyperplasia, routine use of a progestin to prevent endometrial proliferation in women with an intact uterus is not recommended.28 However, these trials were too limited in duration to assure long-term endometrial safety. All postmenopausal women using vaginal ET should be advised to report any vaginal bleeding, and that bleeding should be evaluated appropriately.

JoAnn V. Pinkerton, MD:
I recommend transvaginal ultrasound and endometrial biopsy for women using vaginal estrogen who report spotting or bleeding.

Although low-dose local or vaginal estrogen therapy has not been studied in clinical trials beyond 1 year, it is thought to carry significantly fewer risks than systemic HT.28 Several studies have confirmed that serum estrogen levels remain in the postmenopausal range in women using low-dose vaginal estrogen, specifically the 3-month estradiol ring (2 mg) or twice-weekly estradiol tablets (10 µg).²⁸

Besides relieving vaginal dryness and dyspareunia, low-dose vaginal estrogen also may improve overactive bladder and reduce the incidence of recurrent urinary tract infection.^29,30

CASE: RESOLVED
The 57-year-old patient has been essentially symptom-free for the past 3 years using an estradiol patch (0.075 mg) with progesterone (100 mg nightly). Now she asks how long she should continue HT, and I explain that the duration of bothersome VMS is different in each woman. I also counsel her that hot flushes do resolve over time in almost all women. When she asks how likely it is that bothersome VMS will recur if she simply stops HT, I explain that bothersome symptoms often last 10 years or longer, and I remind her that her VMS began some 4 years earlier.

I also briefly review HT benefits (treatment of VMS as well as prevention of vulvovaginal atrophy and osteoporosis) and risks (small increased risk of breast cancer and stroke). I suggest a reduction in her HT dose as a reasonable method to determine her ongoing need for HT, telling her that she should know within about 1 month how she feels on the lower dose (0.05-mg patch). I also advise her to call my office if bothersome VMS recur on the lower dose so that I can increase the dose back to its original level.

After her estradiol dose is reduced, the patient reports only minimal VMS, and she opts to continue the estradiol patch (0.05 mg) with nightly progesterone (100 mg) for another 2 years.

At age 59, during her well-woman visit, she decides to lower the estradiol further, transitioning to a 0.0375-mg patch but maintaining the nightly progesterone (100 mg). She reports no VMS on this new regimen.

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?

References

Pages

Recommended Reading

Related Articles

Cases in Menopause

Cases in Menopause

Audio

Clinical Review

From the Editor

Audio

Expert Commentary

Expert Commentary