CLIMACTERIC 2015;18:182–186
Ultra-low dose – new approaches in menopausal hormone therapy P. Stute, H.-G. Becker*, J. Bitzer†, D. Chatsiproios‡, F. Luzuy**, M. von Wolff, D. Wunder†† and M. Birkhäuser Department of Obstetrics and Gynecology, University of Berne; *Praxis Dr med. Becker, Uznach; †Department of Obstetrics and Gynecology, University of Basel; ‡Praxis Dr med. Chatsiproios, Kreuzlingen; **Praxis Dr med. Luzuy, Genève; ††CHUV– Département de gynécologie obstétrique et génétique médicale, University of Lausanne, Switzerland
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Key words: MENOPAUSE, HORMONE THERAPY, ULTRA-LOW DOSE, ESTROGEN
ABSTRACT Despite increasing life expectancy, the age of onset of natural menopause has not significantly changed in recent decades. Thus, women spend about one-third of their lives in an estrogen-deficient state if untreated. There is a need for appropriate treatment of acute symptoms and prevention of the sequelae of chronic estrogen deficiency. International guidelines call for the use of the lowest effective hormone dosage for vasomotor symptom relief, the major indication for menopausal hormone therapy (MHT). In 2011, an oral continuous combined ultra-low-dose MHT was approved in Switzerland. This publication was elaborated by eight national menopause specialists and intends to review the advantages and disadvantages of ultra-low-dose MHT after the first years of its general use in Switzerland. It concludes that, for many women, ultra-low-dose MHT may be sufficient to decrease vasomotor symptoms, but not necessarily to guarantee fracture prevention.
INTRODUCTION Despite increasing life expectancy, the age of onset of natural menopause has not significantly changed in recent decades. In the western world, the average age of menopause is 51 years. Thus, most women will survive menopause for almost onethird of their lives, emphasizing the need for an individually appropriate treatment of acute symptoms and prevention of the sequelae of chronic estrogen deficiency. International scientific societies such as the International Menopause Society (IMS)1, the North American Menopause Society2 as well as the Swiss Menopause Society3 recommend the use of the lowest effective estrogen dosage to eliminate symptoms of estrogen deficiency. In 2011, an oral continuous combined ultra-low-dose menopausal hormone therapy (MHT) was approved in Switzerland. This statement was elaborated by eight menopause specialists and intends to review the advantages and disadvantages of ultra-low-dose MHT after the first years of its general use.
THE POST-WHI ERA The Women’s Health Initiative (WHI) was a prospective, randomized, placebo-controlled trial, aiming to assess the risk
and preventive factors associated with the most common causes of death, disability and reduced quality of life in postmenopausal women. The primary outcome was coronary heart disease, and invasive breast cancer was a secondary endpoint. A global index included coronary heart disease, breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes4. Reduction of climacteric symptoms was not a study goal. The mean age of participants was 63.2 years, and at baseline the majority presented with at least one cardiovascular risk factor such as overweight or obesity, arterial hypertension and dyslipidemia. Thus, per definition, the WHI was not a primary prevention trial of cardiovascular disease, and any conclusions drawn with respect to MHT risks in younger women and women without comorbidities are biased. In the WHI, postmenopausal women with an intact uterus were treated with either conjugated equine estrogens (CEE; 0.625 mg/day) combined with medroxyprogesterone acetate (MPA; 2.5 mg/ day) or placebo (WHI-I), while hysterectomized women received either CEE (0.625 mg/day) or placebo (WHI-II), respectively. During the CEE ⫹ MPA intervention phase, risk of invasive breast cancer, stroke, pulmonary embolism and dementia (in women aged ⫺ ⬎ 65 years) was increased while benefits included decreased hip fractures, diabetes, and
Correspondence: Dr P. Stute, Department of Gynecologic Endocrinology and Reproductive Medicine, University Clinic of Obstetrics and Gynecology, Inselspital Berne, Effingerstrasse 102, 3010 Berne, Switzerland; E-mail: [email protected]
OPINION © 2014 International Menopause Society DOI: 10.3109/13697137.2014.975198
Received 26-05-2014 Revised 12-09-2014 Accepted 21-09-2014
Climacteric Downloaded from informahealthcare.com by Nyu Medical Center on 04/25/15 For personal use only.
Ultra-low-dose menopausal hormone therapy vasomotor symptoms5. However, when adjusted for prior MHT use, for example, risk of invasive breast cancer was not significantly increased in MHT-naïve women (hazard ratio (HR) 1.02; 95% confidence interval (CI) 0.77–1.36)6. Most risks and benefits dissipated during the post-intervention phase5. Risks and benefits were more balanced during the CEE-alone intervention. Most importantly, breast cancer risk was non-significantly reduced during the intervention phase and became significant during the cumulative follow-up5. For CEE alone, younger women (aged 50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index5. Similarly, recent data from the Danish Osteoporosis Prevention Study7 and the Nurses’ Health Study8 have confirmed that MHT use does not increase, but decreases the cardiovascular risk and cardiovascular mortality if started in early postmenopausal women within the ‘window of opportunity’9. Furthermore, for combined MHT, breast cancer risk may differ for various progestogens since the prospective observational E3N study reported a ‘safer’ breast profile for estrogens combined with micronized progesterone and dydrogesterone10. However, due to the discontinuation of the WHI-I trial in 2002, an almost panic-like reaction towards the use of MHT led to a drastic decline of the prevalence and incidence of MHT prescriptions11. Accordingly (inter)national guidelines for MHT use have been modified, with the main indication being relief of vasomotor symptoms and treatment of symptomatic vaginal atrophy12–14. However, the guidelines from the IMS1,15 and from the Swiss Menopause Society3 also state that MHT may be used to prevent osteoporosis-associated fractures. Since 2002, MHT development has continuously progressed, and numerous oral and transdermal MHT preparations are available today at varying estrogen dosages and combined with various progestogen types.
ULTRA-LOW-DOSE MHT For vasomotor symptom relief, estrogens are recommended at the lowest effective dosage1–3. A previous 12-week trial investigating the efficacy of varying oral estradiol dosages, ranging from 0.25 mg/day to 2 mg/day, revealed that at least 0.5 mg estradiol/day is necessary to sufficiently decrease vasomotor symptoms16. In women with an intact uterus, estrogens should be combined with a progestogen for protection of the endometrium. In the past, often the lowest effective MHT dosage could only be achieved by splitting tablets, cutting dermal patches, or by prolongation of the dosing interval. However, the off-label use of approved standard- or low-dose MHT preparations is not ideal in terms of pharmaceutical galenics and safety, due to the lack of studies for this kind of ‘selfmade’ ultra-low-dose MHT. Until recently, ultra-low-dose combined MHT has been successfully used in clinical trials, but has not been introduced for general use until 2011. Since then, a fixed oral combined ultra-low-dose MHT containing 0.5 mg 17β-estradiol and 2.5 mg dydrogesterone is available. Efficacy and safety were assessed in a 52-week, randomized,
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Stute et al. placebo-controlled trial in 313 postmenopausal healthy women aged 54 years on average. Participants were randomized to (1) 0.5 mg 17β-estradiol combined with 2.5 mg dydrogesterone, (2) 1 mg 17β-estradiol combined with 5 mg dydrogesterone, or (3) placebo. Both ultra-low-dose and lowdose MHT significantly reduced moderate to severe vasomotor symptoms17. Similarly, the 24-week, randomized, placebocontrolled trial CHOICE demonstrated a significant reduction of vasomotor symptoms by 0.5 mg 17β-estradiol combined with either 0.1 mg or 0.25 mg norethindrone acetate (NETA), in 577 postmenopausal healthy women aged 55.5 years on average18. The rate of amenorrhea was approximately 90% after 6 months19 and 1 year17. Endometrial safety was assessed either by endometrial biopsy prior to and after 52 weeks of treatment20, or by vaginal ultrasound measuring endometrial thickness19. After 1 year of treatment with 0.5 mg 17β-estradiol combined with 2.5 mg dydrogesterone, one woman developed a simple hyperplasia which was within the range of the guidelines of the Committee for Medicinal Products for Human Use for the conclusion of endometrial safety for new MHT regimens20. Overall, ultra-low-dose MHT was well tolerated and rare side-effects were limited to uterine bleeding, mastopathy and breast discomfort or pain. There were no cases of venous thromboembolism17,18. Thus, based on existing data, it can be assumed that ultra-low-dose MHT tends to be associated with fewer risks than low-dose MHT, even though this remains to be formally proven.
LONG-TERM BENEFITS AND LIMITATIONS OF ULTRA-LOW-DOSE MHT To date, there are no direct head-to-head trials comparing long-term safety of standard-dose, low-dose and ultra-lowdose MHT. It appears reasonable to assume that a lower hormone dosage would be associated with fewer estrogenic and especially progestogenic side-effects21 as well as fewer safety concerns, but this has not been conclusively demonstrated. So far, for example, the Nurses’ Health Study has demonstrated a lack of increased risk of stroke for ultra-lowdose treatment with CEE22,23. In a nested case–control study based on the United Kingdom’s General Practice Research Database, no increased risk of stroke has been observed in users of transdermal MHT containing low doses of estrogen24 whereas, in users of oral MHT, risk was dose-dependent. In the Danish Nurses’ Study, stroke risk did not increase in normotensive compared to hypertensive users of oral MHT25. A recent review has shown that transdermal estrogens are not associated with a higher risk of recurrent venous thromboembolism among postmenopausal women, and that, for oral MHT, the dose of estrogens is an important determinant of the thrombotic risk among postmenopausal women using MHT26. Furthermore, the ESTHER study has revealed an increased risk of venous thromboembolism for the use of norpregnane derivatives but not for the use of micronized progesterone and pregnane derivatives27. Finally, preliminary studies with surrogate parameters as endpoints indicate that,
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Ultra-low-dose menopausal hormone therapy in contrast to standard-dose MHT, mammographic density remains almost unchanged during 6 months’ treatment with ultra-low-dose 17β-estradiol combined with NETA28,29. However, until there are studies demonstrating a better longterm safety profile for ultra-low-dose MHT, risks associated with long-term standard-dose MHT are also applicable to ultra-low-dose MHT. It is unknown whether ultra-low-dose MHT is sufficient for preservation of bone mass and reduction of fracture risk in postmenopausal women. In the USA, an ultra-low-dose estrogen patch (0.014 mg estradiol/day) has been approved by the FDA for osteoporosis prevention30. Similarly, oral ultralow-dose MHT with 0.5 mg 17β-estradiol combined with 0.25 mg NETA/day for 2 years equally increased bone mineral density (BMD) at the lumbar spine and hip when compared to low-dose MHT31. On the contrary, an increased rate of non-responders (defined as more than 2% loss in lumbar spine BMD during treatment) was reported for ultra-low-dose MHT with 0.25 mg (22%) and 0.5 mg (13%) estradiol/day, while treatment with 1 mg estradiol/day alone (8%) or combined with NETA (3–8%) had a much lower rate32. So far, there are no data on fracture risk in postmenopausal women using ultra-low-dose MHT. Thus, if fracture risk reduction in osteopenic or osteoporotic postmenopausal women is a therapeutic goal, individual BMD monitoring of a patient using ultra-low-dose MHT is recommended for prompt identification of women requiring treatment modifications.
WHEN SHOULD ULTRA-LOW-DOSE MHT BE STARTED? One of the most important results from the WHI is the observation that the risk of coronary heart disease events depends on age and years since menopause when MHT is initiated33. If MHT is initiated within 10 years after menopause, risk of coronary heart disease is lower than if MHT is initiated more than 20 years after menopause (⬍ 10 years since menopause: HR 0.76; 95% CI 0.50–1.16; ⫺ ⬎ 20 years since menopause: HR 1.28; 95% CI 1.03–1.58)34. A meta-analysis of 39 studies in more than 39 000 women came to a similar conclusion35. The finding that timing of estrogen initiation is crucial for the female heart is called the ‘timing hypothesis’, which means that MHT has differential effects on early and later stages of atherosclerotic disease9. The ‘timing hypothesis’ is supported by studies in non-human primates36. However, in humans, so far, the timing hypothesis applies to one standard dose of estrogen: 0.625 mg of CEE per day. The adverse cardiovascular effects seen with initiation of MHT in women aged ⬎ 60 years may reflect that the dose was inappropriately high for their age rather than the stage of atherosclerosis was differentially affected by the estrogen. Although there are no data for women using ultra-low-dose MHT, it might be speculated that combined ultra-low-dose MHT with 17β-estradiol and dydrogesterone will have comparable long-term effects on the female heart as standard-dose MHT with progesterone or dydrogesterone.
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SWITCHING FROM SEQUENTIAL TO CONTINUOUS COMBINED ULTRA-LOWDOSE MHT When initiating MHT, the lowest effective dosage for symptom control is recommended. For one in two patients, ultra-lowdose MHT is sufficient to achieve this target37, while others require a higher initial hormone dosage. For women with an intact uterus, estrogens should to be combined with a progestogen, either sequentially or continuously. Continuous combined MHT prevents the build-up of the uterine lining which ultimately leads to menstruation cessation. In contrast, sequential MHT leads to a withdrawal bleeding during the progestogen-free interval. In general, sequential MHT use is recommended for the perimenopause and early postmenopause1,3. Continuous combined MHT is generally initiated following a sequential MHT strategy. If the main goal of MHT is to relieve vasomotor symptoms, switching to continuous combined ultra-low-dose MHT may be indicated after the initial treatment with sequential low-dose MHT, sequential ultra-lowdose MHT or continuous combined MHT, to reduce exogenous hormone exposure to a minimal level. Thus, a change to continuous combined ultra-low-dose MHT may be considered 2–3 years after menopause (Figure 1). However, there are no universally valid criteria or procedures for switching from sequential or continuous combined standard-dose or low-dose MHT to continuous combined ultra-low-dose MHT. Again, the highly individual nature of MHT becomes evident. It is essential to extensively inform patients about the possibility of bleeding events within the first 6 months after switching to a MHT regime. If reducing hormone dosage leads to regular hot flushes again, which do not resolve within the first 14 days after switching to ultra-low-dose MHT, patients are likely to discontinue. In those women, re-increasing the hormone dosage should be considered and discussed.
CONCLUSION The primary indication for MHT is relief of vasomotor symptoms. Individual risks and benefits should be weighed, and the lowest effective hormone dosage be chosen. For many women, ultra-low-dose MHT may be sufficient to decrease vasomotor symptoms, but not necessarily to guarantee fracture prevention. Possibly, ultra-low-dose MHT might be a compromise for those women who are more critical towards MHT but in whom alternative and complementary medicine strategies have not been successful. Comparable to standard-dose and low-dose MHT, bleeding events may occur when initiating ultra-low-dose MHT and may require individual dosage adjustments. For women treated with high- or standard-dose MHT, switching progressively to lowdose and then to ultra-low-dose MHT may be a good way to lower hormone dosage without compromising vasomotor symptom relief before stopping MHT as soon as it is needed no more. Furthermore, the type of the progestogen seems to
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Ultra-low-dose menopausal hormone therapy
Stute et al.
ccLD-MHT or seqLD-MHT or ccULD-MHT for symptom control
Switching to ccULD-MHT can be considered
Window of Opportunity
premenopause
postmenopause
Concentration in the blood
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estrogen
perimenopause After age 60: Initiate or switch to ULD MHT or phase out MHT.
progesterone
45
50
55
60
65
Age (years)
Figure 1 Treatment algorithm for menopausal hormone therapy (MHT). MHT should be adjusted to suit the individual needs of a patient. The presented algorithm is, therefore, only intended as a guide. To ensure endometrial safety, a progestogen should always be combined with estrogens in women with an intact uterus. If continuous combined ultra-low-dose MHT is chosen for treatment initiation, bleeding events may occur initially. ULD, ultra-low dose; LD, low dose; cc, continuous combined; seq, sequential
be another important determinant of the long-term risk of MHT. Micronized progesterone and pregnane derivatives, including dydrogesterone, might be metabolically more favorable than norpregane derivatives. Ideally, MHT should be initiated in the perimenopause or early postmenopause but not 10 or more years after menopause as atherosclerotic changes are likely to have occurred by then, increasing, for example, the risk of myocardial infarction. However, individual needs and risk factors have to be considered for each patient during the decision-making process. The introduction of continuous combined ultra-low-dose MHT enlarge our possibilities to individualize the treatment of symptomatic postmenopausal women. Thus, the risk can be avoided of serum hormone fluctuations arising from the previous
practice of splitting tablets or cutting patches to reduce the hormone dosage of low-dose MHT.
ACKNOWLEDGEMENT The authors thank PR-Schwegler AG, Agency for Health Care Communications Zürich, for preparing the figure material. Conflict of interest The authors have been part of the Swiss expert board funded by Abbott AG. Source of funding This publication was developed by a Swiss expert board and was funded by Abbott AG by an unrestricted grant without influence on the content.
References 1. Sturdee DW, Pines A, Archer DF, et al. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric 2011;14: 302–20 2. North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19:257–71
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3. Bodmer C, Steimann S, Schiessl K, De Geyter C, Imthurn B, Birkhäuser M. Hormonersatztherapie (HET) – Guidelines für die Schweiz. J Gynäkol Endokrinol 2009;3:26–30 4. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33
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Ultra-low-dose menopausal hormone therapy 5. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 2013;310:1353–68 6. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55:103–15 7. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345:e6409 8. Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Women’s Health 2006;15:35–44 9. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583–7 10. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treatment 2008;107:103–11 11. Ettinger B, Wang SM, Leslie RS, et al. Evolution of postmenopausal hormone therapy between 2002 and 2009. Menopause 2012;19:610–15 12. American College of Obstetricians, Gynecologists Women’s Health Care Physicians. Executive summary. Hormone therapy. Obstet Gynecol 2004;104(4 Suppl):1–4S 13. North American Menopause Society. Recommendations for estrogen and progestogen use in peri- and postmenopausal women: October 2004 position statement of The North American Menopause Society. Menopause 2004;11:589–600 14. U.S. Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women. Ann Intern Med 2005;142:855–60 15. de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013;16:316–37 16. Notelovitz M, Lenihan J, McDermott M, Kerber I, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000;95:726–31 17. Stevenson JC, Durand G, Kahler E, Perty ski T. Oral ultra-low dose continuous combined hormone replacement therapy with 0.5mg 17β-oestradiol and 2.5mg dydrogesterone for the treatment of vasomotor symptoms: Results from a double-blind, controlled study. Maturitas 2010;67:227–32 18. Panay N, Ylikorkala O, Archer DF, Gut R, Lang E. Ultra-lowdose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric 2007;10:120–31 19. Sturdee DW, Archer DF, Rakov V, Lang E. Ultra-low-dose continuous combined estradiol and norethisterone acetate: improved bleeding profile in postmenopausal women. Climacteric 2008;11:63–73 20. Bergeron C, Nogales FF, Rechberger T, Tatarchjuk T, Zipfel L. Ultra low dose continuous combined hormone replacement therapy with 0.5 mg 17β-oestradiol and 2.5 mg dydrogesterone: protection of the endometrium and amenorrhoea rate. Maturitas 2010;66:201–5 21. Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997;3:159–71
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Stute et al. 22. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133: 933–41 23. Grodstein F, Manson JE, Stampfer MJ, Rexrode K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. Arch Intern Med 2008;168:861–6 24. 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 25. Lokkegaard E, Jovanovic Z, Heitmann BL, et al. Increased risk of stroke in hypertensive women using hormone therapy: analyses based on the Danish Nurse Study. Arch Neurol 2003; 60:1379–84 26. Olie V, Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause 2011; 18:488–93 27. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840–5 28. Grady D, Vittinghoff E, Lin F, et al. Effect of ultra-low-dose transdermal estradiol on breast density in postmenopausal women. Menopause 2007;14:391–6 29. Lundstrom E, Bygdeson M, Svane G, Azavedo E, von Schoultz B. Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density. Climacteric 2007;10:249–56 30. Ettinger B, Ensrud KE, Wallace R, et al. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol 2004;104:443–51 31. Gambacciani M, Cappagli B, Ciaponi M, Pepe A, Vacca F, Genazzani AR. Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women. Maturitas 2008;59:2–6 32. McClung M. Osteoporosis prevention. Presented at American Society for Bone and Mineral Research, San Francisco,1998 33. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297:1465–77 34. Hodis HN, Collins P, Mack WJ, Schierbeck LL. The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective. Climacteric 2012;15:217–28 35. Salpeter SR, Walsh JM, Greyber E, Salpeter EE. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med 2006;21:363–6 36. Clarkson TB, Melendez GC, Appt SE. Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future. Menopause 2013;20:342–53 37. Johansen OE, Qvigstad E. Rationale for low-dose systemic hormone replacement therapy and review of estradiol 0.5 mg/NETA 0.1 mg. Adv Therapy 2008;25:525–51
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Ultra-low dose – new approaches in menopausal hormone therapy P. Stute, H.-G. Becker*, J. Bitzer†, D. Chatsiproios‡, F. Luzuy**, M. von Wolff, D. Wunder†† and M. Birkhäuser Department of Obstetrics and Gynecology, University of Berne; *Praxis Dr med. Becker, Uznach; †Department of Obstetrics and Gynecology, University of Basel; ‡Praxis Dr med. Chatsiproios, Kreuzlingen; **Praxis Dr med. Luzuy, Genève; ††CHUV– Département de gynécologie obstétrique et génétique médicale, University of Lausanne, Switzerland
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Key words: MENOPAUSE, HORMONE THERAPY, ULTRA-LOW DOSE, ESTROGEN
ABSTRACT Despite increasing life expectancy, the age of onset of natural menopause has not significantly changed in recent decades. Thus, women spend about one-third of their lives in an estrogen-deficient state if untreated. There is a need for appropriate treatment of acute symptoms and prevention of the sequelae of chronic estrogen deficiency. International guidelines call for the use of the lowest effective hormone dosage for vasomotor symptom relief, the major indication for menopausal hormone therapy (MHT). In 2011, an oral continuous combined ultra-low-dose MHT was approved in Switzerland. This publication was elaborated by eight national menopause specialists and intends to review the advantages and disadvantages of ultra-low-dose MHT after the first years of its general use in Switzerland. It concludes that, for many women, ultra-low-dose MHT may be sufficient to decrease vasomotor symptoms, but not necessarily to guarantee fracture prevention.
INTRODUCTION Despite increasing life expectancy, the age of onset of natural menopause has not significantly changed in recent decades. In the western world, the average age of menopause is 51 years. Thus, most women will survive menopause for almost onethird of their lives, emphasizing the need for an individually appropriate treatment of acute symptoms and prevention of the sequelae of chronic estrogen deficiency. International scientific societies such as the International Menopause Society (IMS)1, the North American Menopause Society2 as well as the Swiss Menopause Society3 recommend the use of the lowest effective estrogen dosage to eliminate symptoms of estrogen deficiency. In 2011, an oral continuous combined ultra-low-dose menopausal hormone therapy (MHT) was approved in Switzerland. This statement was elaborated by eight menopause specialists and intends to review the advantages and disadvantages of ultra-low-dose MHT after the first years of its general use.
THE POST-WHI ERA The Women’s Health Initiative (WHI) was a prospective, randomized, placebo-controlled trial, aiming to assess the risk
and preventive factors associated with the most common causes of death, disability and reduced quality of life in postmenopausal women. The primary outcome was coronary heart disease, and invasive breast cancer was a secondary endpoint. A global index included coronary heart disease, breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes4. Reduction of climacteric symptoms was not a study goal. The mean age of participants was 63.2 years, and at baseline the majority presented with at least one cardiovascular risk factor such as overweight or obesity, arterial hypertension and dyslipidemia. Thus, per definition, the WHI was not a primary prevention trial of cardiovascular disease, and any conclusions drawn with respect to MHT risks in younger women and women without comorbidities are biased. In the WHI, postmenopausal women with an intact uterus were treated with either conjugated equine estrogens (CEE; 0.625 mg/day) combined with medroxyprogesterone acetate (MPA; 2.5 mg/ day) or placebo (WHI-I), while hysterectomized women received either CEE (0.625 mg/day) or placebo (WHI-II), respectively. During the CEE ⫹ MPA intervention phase, risk of invasive breast cancer, stroke, pulmonary embolism and dementia (in women aged ⫺ ⬎ 65 years) was increased while benefits included decreased hip fractures, diabetes, and
Correspondence: Dr P. Stute, Department of Gynecologic Endocrinology and Reproductive Medicine, University Clinic of Obstetrics and Gynecology, Inselspital Berne, Effingerstrasse 102, 3010 Berne, Switzerland; E-mail: [email protected]
OPINION © 2014 International Menopause Society DOI: 10.3109/13697137.2014.975198
Received 26-05-2014 Revised 12-09-2014 Accepted 21-09-2014
Climacteric Downloaded from informahealthcare.com by Nyu Medical Center on 04/25/15 For personal use only.
Ultra-low-dose menopausal hormone therapy vasomotor symptoms5. However, when adjusted for prior MHT use, for example, risk of invasive breast cancer was not significantly increased in MHT-naïve women (hazard ratio (HR) 1.02; 95% confidence interval (CI) 0.77–1.36)6. Most risks and benefits dissipated during the post-intervention phase5. Risks and benefits were more balanced during the CEE-alone intervention. Most importantly, breast cancer risk was non-significantly reduced during the intervention phase and became significant during the cumulative follow-up5. For CEE alone, younger women (aged 50–59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index5. Similarly, recent data from the Danish Osteoporosis Prevention Study7 and the Nurses’ Health Study8 have confirmed that MHT use does not increase, but decreases the cardiovascular risk and cardiovascular mortality if started in early postmenopausal women within the ‘window of opportunity’9. Furthermore, for combined MHT, breast cancer risk may differ for various progestogens since the prospective observational E3N study reported a ‘safer’ breast profile for estrogens combined with micronized progesterone and dydrogesterone10. However, due to the discontinuation of the WHI-I trial in 2002, an almost panic-like reaction towards the use of MHT led to a drastic decline of the prevalence and incidence of MHT prescriptions11. Accordingly (inter)national guidelines for MHT use have been modified, with the main indication being relief of vasomotor symptoms and treatment of symptomatic vaginal atrophy12–14. However, the guidelines from the IMS1,15 and from the Swiss Menopause Society3 also state that MHT may be used to prevent osteoporosis-associated fractures. Since 2002, MHT development has continuously progressed, and numerous oral and transdermal MHT preparations are available today at varying estrogen dosages and combined with various progestogen types.
ULTRA-LOW-DOSE MHT For vasomotor symptom relief, estrogens are recommended at the lowest effective dosage1–3. A previous 12-week trial investigating the efficacy of varying oral estradiol dosages, ranging from 0.25 mg/day to 2 mg/day, revealed that at least 0.5 mg estradiol/day is necessary to sufficiently decrease vasomotor symptoms16. In women with an intact uterus, estrogens should be combined with a progestogen for protection of the endometrium. In the past, often the lowest effective MHT dosage could only be achieved by splitting tablets, cutting dermal patches, or by prolongation of the dosing interval. However, the off-label use of approved standard- or low-dose MHT preparations is not ideal in terms of pharmaceutical galenics and safety, due to the lack of studies for this kind of ‘selfmade’ ultra-low-dose MHT. Until recently, ultra-low-dose combined MHT has been successfully used in clinical trials, but has not been introduced for general use until 2011. Since then, a fixed oral combined ultra-low-dose MHT containing 0.5 mg 17β-estradiol and 2.5 mg dydrogesterone is available. Efficacy and safety were assessed in a 52-week, randomized,
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Stute et al. placebo-controlled trial in 313 postmenopausal healthy women aged 54 years on average. Participants were randomized to (1) 0.5 mg 17β-estradiol combined with 2.5 mg dydrogesterone, (2) 1 mg 17β-estradiol combined with 5 mg dydrogesterone, or (3) placebo. Both ultra-low-dose and lowdose MHT significantly reduced moderate to severe vasomotor symptoms17. Similarly, the 24-week, randomized, placebocontrolled trial CHOICE demonstrated a significant reduction of vasomotor symptoms by 0.5 mg 17β-estradiol combined with either 0.1 mg or 0.25 mg norethindrone acetate (NETA), in 577 postmenopausal healthy women aged 55.5 years on average18. The rate of amenorrhea was approximately 90% after 6 months19 and 1 year17. Endometrial safety was assessed either by endometrial biopsy prior to and after 52 weeks of treatment20, or by vaginal ultrasound measuring endometrial thickness19. After 1 year of treatment with 0.5 mg 17β-estradiol combined with 2.5 mg dydrogesterone, one woman developed a simple hyperplasia which was within the range of the guidelines of the Committee for Medicinal Products for Human Use for the conclusion of endometrial safety for new MHT regimens20. Overall, ultra-low-dose MHT was well tolerated and rare side-effects were limited to uterine bleeding, mastopathy and breast discomfort or pain. There were no cases of venous thromboembolism17,18. Thus, based on existing data, it can be assumed that ultra-low-dose MHT tends to be associated with fewer risks than low-dose MHT, even though this remains to be formally proven.
LONG-TERM BENEFITS AND LIMITATIONS OF ULTRA-LOW-DOSE MHT To date, there are no direct head-to-head trials comparing long-term safety of standard-dose, low-dose and ultra-lowdose MHT. It appears reasonable to assume that a lower hormone dosage would be associated with fewer estrogenic and especially progestogenic side-effects21 as well as fewer safety concerns, but this has not been conclusively demonstrated. So far, for example, the Nurses’ Health Study has demonstrated a lack of increased risk of stroke for ultra-lowdose treatment with CEE22,23. In a nested case–control study based on the United Kingdom’s General Practice Research Database, no increased risk of stroke has been observed in users of transdermal MHT containing low doses of estrogen24 whereas, in users of oral MHT, risk was dose-dependent. In the Danish Nurses’ Study, stroke risk did not increase in normotensive compared to hypertensive users of oral MHT25. A recent review has shown that transdermal estrogens are not associated with a higher risk of recurrent venous thromboembolism among postmenopausal women, and that, for oral MHT, the dose of estrogens is an important determinant of the thrombotic risk among postmenopausal women using MHT26. Furthermore, the ESTHER study has revealed an increased risk of venous thromboembolism for the use of norpregnane derivatives but not for the use of micronized progesterone and pregnane derivatives27. Finally, preliminary studies with surrogate parameters as endpoints indicate that,
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Ultra-low-dose menopausal hormone therapy in contrast to standard-dose MHT, mammographic density remains almost unchanged during 6 months’ treatment with ultra-low-dose 17β-estradiol combined with NETA28,29. However, until there are studies demonstrating a better longterm safety profile for ultra-low-dose MHT, risks associated with long-term standard-dose MHT are also applicable to ultra-low-dose MHT. It is unknown whether ultra-low-dose MHT is sufficient for preservation of bone mass and reduction of fracture risk in postmenopausal women. In the USA, an ultra-low-dose estrogen patch (0.014 mg estradiol/day) has been approved by the FDA for osteoporosis prevention30. Similarly, oral ultralow-dose MHT with 0.5 mg 17β-estradiol combined with 0.25 mg NETA/day for 2 years equally increased bone mineral density (BMD) at the lumbar spine and hip when compared to low-dose MHT31. On the contrary, an increased rate of non-responders (defined as more than 2% loss in lumbar spine BMD during treatment) was reported for ultra-low-dose MHT with 0.25 mg (22%) and 0.5 mg (13%) estradiol/day, while treatment with 1 mg estradiol/day alone (8%) or combined with NETA (3–8%) had a much lower rate32. So far, there are no data on fracture risk in postmenopausal women using ultra-low-dose MHT. Thus, if fracture risk reduction in osteopenic or osteoporotic postmenopausal women is a therapeutic goal, individual BMD monitoring of a patient using ultra-low-dose MHT is recommended for prompt identification of women requiring treatment modifications.
WHEN SHOULD ULTRA-LOW-DOSE MHT BE STARTED? One of the most important results from the WHI is the observation that the risk of coronary heart disease events depends on age and years since menopause when MHT is initiated33. If MHT is initiated within 10 years after menopause, risk of coronary heart disease is lower than if MHT is initiated more than 20 years after menopause (⬍ 10 years since menopause: HR 0.76; 95% CI 0.50–1.16; ⫺ ⬎ 20 years since menopause: HR 1.28; 95% CI 1.03–1.58)34. A meta-analysis of 39 studies in more than 39 000 women came to a similar conclusion35. The finding that timing of estrogen initiation is crucial for the female heart is called the ‘timing hypothesis’, which means that MHT has differential effects on early and later stages of atherosclerotic disease9. The ‘timing hypothesis’ is supported by studies in non-human primates36. However, in humans, so far, the timing hypothesis applies to one standard dose of estrogen: 0.625 mg of CEE per day. The adverse cardiovascular effects seen with initiation of MHT in women aged ⬎ 60 years may reflect that the dose was inappropriately high for their age rather than the stage of atherosclerosis was differentially affected by the estrogen. Although there are no data for women using ultra-low-dose MHT, it might be speculated that combined ultra-low-dose MHT with 17β-estradiol and dydrogesterone will have comparable long-term effects on the female heart as standard-dose MHT with progesterone or dydrogesterone.
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SWITCHING FROM SEQUENTIAL TO CONTINUOUS COMBINED ULTRA-LOWDOSE MHT When initiating MHT, the lowest effective dosage for symptom control is recommended. For one in two patients, ultra-lowdose MHT is sufficient to achieve this target37, while others require a higher initial hormone dosage. For women with an intact uterus, estrogens should to be combined with a progestogen, either sequentially or continuously. Continuous combined MHT prevents the build-up of the uterine lining which ultimately leads to menstruation cessation. In contrast, sequential MHT leads to a withdrawal bleeding during the progestogen-free interval. In general, sequential MHT use is recommended for the perimenopause and early postmenopause1,3. Continuous combined MHT is generally initiated following a sequential MHT strategy. If the main goal of MHT is to relieve vasomotor symptoms, switching to continuous combined ultra-low-dose MHT may be indicated after the initial treatment with sequential low-dose MHT, sequential ultra-lowdose MHT or continuous combined MHT, to reduce exogenous hormone exposure to a minimal level. Thus, a change to continuous combined ultra-low-dose MHT may be considered 2–3 years after menopause (Figure 1). However, there are no universally valid criteria or procedures for switching from sequential or continuous combined standard-dose or low-dose MHT to continuous combined ultra-low-dose MHT. Again, the highly individual nature of MHT becomes evident. It is essential to extensively inform patients about the possibility of bleeding events within the first 6 months after switching to a MHT regime. If reducing hormone dosage leads to regular hot flushes again, which do not resolve within the first 14 days after switching to ultra-low-dose MHT, patients are likely to discontinue. In those women, re-increasing the hormone dosage should be considered and discussed.
CONCLUSION The primary indication for MHT is relief of vasomotor symptoms. Individual risks and benefits should be weighed, and the lowest effective hormone dosage be chosen. For many women, ultra-low-dose MHT may be sufficient to decrease vasomotor symptoms, but not necessarily to guarantee fracture prevention. Possibly, ultra-low-dose MHT might be a compromise for those women who are more critical towards MHT but in whom alternative and complementary medicine strategies have not been successful. Comparable to standard-dose and low-dose MHT, bleeding events may occur when initiating ultra-low-dose MHT and may require individual dosage adjustments. For women treated with high- or standard-dose MHT, switching progressively to lowdose and then to ultra-low-dose MHT may be a good way to lower hormone dosage without compromising vasomotor symptom relief before stopping MHT as soon as it is needed no more. Furthermore, the type of the progestogen seems to
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Ultra-low-dose menopausal hormone therapy
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ccLD-MHT or seqLD-MHT or ccULD-MHT for symptom control
Switching to ccULD-MHT can be considered
Window of Opportunity
premenopause
postmenopause
Concentration in the blood
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estrogen
perimenopause After age 60: Initiate or switch to ULD MHT or phase out MHT.
progesterone
45
50
55
60
65
Age (years)
Figure 1 Treatment algorithm for menopausal hormone therapy (MHT). MHT should be adjusted to suit the individual needs of a patient. The presented algorithm is, therefore, only intended as a guide. To ensure endometrial safety, a progestogen should always be combined with estrogens in women with an intact uterus. If continuous combined ultra-low-dose MHT is chosen for treatment initiation, bleeding events may occur initially. ULD, ultra-low dose; LD, low dose; cc, continuous combined; seq, sequential
be another important determinant of the long-term risk of MHT. Micronized progesterone and pregnane derivatives, including dydrogesterone, might be metabolically more favorable than norpregane derivatives. Ideally, MHT should be initiated in the perimenopause or early postmenopause but not 10 or more years after menopause as atherosclerotic changes are likely to have occurred by then, increasing, for example, the risk of myocardial infarction. However, individual needs and risk factors have to be considered for each patient during the decision-making process. The introduction of continuous combined ultra-low-dose MHT enlarge our possibilities to individualize the treatment of symptomatic postmenopausal women. Thus, the risk can be avoided of serum hormone fluctuations arising from the previous
practice of splitting tablets or cutting patches to reduce the hormone dosage of low-dose MHT.
ACKNOWLEDGEMENT The authors thank PR-Schwegler AG, Agency for Health Care Communications Zürich, for preparing the figure material. Conflict of interest The authors have been part of the Swiss expert board funded by Abbott AG. Source of funding This publication was developed by a Swiss expert board and was funded by Abbott AG by an unrestricted grant without influence on the content.
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