Menopause: The Journal of The North American Menopause Society Vol. 21, No. 3, pp. 211/212 DOI: 10.1097/gme.0000000000000212 * 2014 by The North American Menopause Society

EDITORIAL Has the pendulum begun to swing back? he article by Archer et al1 in this issue of Menopause details a study of combination hormone therapies containing drospirenone (DRSP) and 17A-estradiol (E2) to determine the lowest effective daily doses of DRSP and E2 for the treatment of moderate to severe vasomotor symptoms in postmenopausal women. Although the premise of such a study is not novel and the specific estrogen-progestin components of the study pill regimens have been found in approved and available combination menopausal regimens for many years, they relay that the current 12-week placebo-controlled study was performed at the behest of the BI US Regulatory Agency to characterize the lowest effective dose combination of DRSP/E2 for relief of moderate to severe vasomotor symptoms.[ The outcome of the study is thus of interest to the readers of Menopause and to all those who provide health care to postmenopausal women; however, this study has greater implications than simply the determination of a minimally effective dose of sex steroids for the treatment of menopausal vasomotor symptoms. Rather, the publication of this study is one sign that hormone therapy may again be considered by women and clinicians as a popular option for the treatment of menopausal symptoms. Some may be surprised by this statement; that is, many of the readers of Menopause and other clinicians use hormone therapies for the treatment of menopausal symptoms in clinically appropriate women who have been counseled about the benefits and risks of such therapies. However, many clinicians who provide care to postmenopausal women may not be as well versed in the considerable literature concerning symptomatic postmenopausal women and may continue to subliminally and actively dissuade and discourage women from using hormone therapies, especially systemic regimens. During the past decade, I have seen in my office many women who report that their physician actually refused to provide systemic or local hormone therapy for the treatment of menopausal symptoms, even though there were no relative or absolute contraindications to the use of such therapies. Such actions feed into the popular perception that hormone therapies are not safe and that their use is associated with far more risks than benefits. Every day in my office, when I bring up the topic of hormone therapy with a symptomatic woman, the response of that woman is a look of incredulity combined with a question along the lines of BI are you sure?[ orVwith apologies to the script writers of the 1976 movie Marathon ManVBI is it safe?[ Much of this continuing resistance to the use of menopausal hormone therapies seems to arise from the initial report of the results from the Women’s Health Initiative (WHI) in 2002.2 Despite further analyses of the WHI database (which have

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shown different and far more salutary clinical outcomes3 than those initially reported) and considerable literature showing a different physiological effect of nonoral hormonal regimens compared with oral regimens,4 the use of hormone therapies for the treatment of menopausal symptoms continues to decline in spite of increases in the number of symptomatic postmenopausal women.5 Although this decline in use has led to the development of alternative methods, many of those therapies are associated with only a modest improvement in symptoms along with adverse effect profiles that many women find problematic.6 In addition, the fear of menopausal hormone therapy has also supported the burgeoning industry of Bnatural[ or botanical products that have mostly been shown to have little to no benefit compared with placebo7 but are vigorously promoted by a disparate array of celebrities, self-proclaimed women’s advocates, and othersVall of whom are either unfamiliar with the concept of a robust clinical trial or well-versed with ignoring such mundane and archaic information and processes required for the proper assessment of the effectiveness and safety of a clinical intervention. Unfortunately, all too many women and clinicians believe that the absence of safety data is indicative of the absence of safety concerns and that products sold over-thecounter (and through the Internet) must be effective and safe, especially if a celebrity is promoting their use and no prescription is required for purchase. Thus, into this environment comes this study by Archer et al,1 supported by Bayer Pharma AG, which seeks to determine the lowest effective dose of DRSP with E2 for moderate to severe vasomotor symptoms in postmenopausal women. For me, the importance of this study is that a pharmaceutical company involved in the development and marketing of women’s healthcare products decided to proceed with a study of a lowdose oral combination hormone therapy for the treatment of menopausal vasomotor symptoms. Why is this important? A study of a combination oral hormone therapy composed of components that are already found in a Food and Drug AdministrationYapproved regimen for the treatment of menopausal symptoms is hardly the subject matter of journal editorials. However, that a pharmaceutical company has supported a study that would potentially lead to the development of a new oral hormone therapy for menopausal symptoms is noteworthy. As stated earlier, the use of systemic hormone therapies has continued to decline since the publication of the initial findings from the WHI.2 Accordingly, the desire to develop and market such a product would indicate that the company had identified an unmet need that this product would address. The company has probably undertaken Menopause, Vol. 21, No. 3, 2014

Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.

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market research indicating that appropriately screened and counseled symptomatic women would consider a low-dose combination oral hormone therapy. Given that the current class labeling that continues to be applied to essentially all menopausal hormone therapies (regardless of components, dose, or mode of delivery) is characterized by a lack of any substantive evidence that such labeling represents an accurate assessment of the actual safety of a specific systemic or local hormone therapy,8 the introduction of a new low-dose combination oral regimen would have clear hurdles to overcome. As such, the industry’s commitment to provide more therapeutic options is laudable and indicative of the potential of such a therapy to become a regimen used by women seeking relief from their menopause-related symptoms. The one caveat in my reading of this study is that, although the development and use of pharmacological therapeutic options typically and appropriately seek to find and use the lowest effective dose for the shortest period (an approach to the initiation of hormone therapy supported by a recent position paper from The North American Menopause Society9), the lowest effective dosing regimen for a specific clinical outcome may not necessarily represent the regimen with optimal tolerability, overall clinical impact, or even safety. Indeed, Archer et al1 present a variety of clinical benefits associated with higher-dose combinations of E2 and DRSP in menopausal therapies available outside the United States and discuss the need for higherdose combinations of DRSP/E2 for Bthose women who do not respond to 0.25 mg DRSP/0.5 mg E2 by week 6 of treatment.[ It is important to remember that drug development is not a simple combination of active and inert ingredients that have been identified as a result of pharmacokinetic studies. Drug development is a complicated and complex process that involves a wide array of pharmacological, physiological, clinical, and patient-based factors andVdepending on the desired clinical outcomesVmay require dosing that is greater than the minimally effective dose, as observed with the development of many hormonal contraceptives. Nonetheless, all drugs must go through a rigorous assessment for effectiveness, adverse effect profile, and overall safety (short term and long term) so that patients and clinicians can have an accurate assessment of the potential benefits and risks of a particular therapeutic intervention. This study is a seminal component of that process; also needed are more robust evaluations of the actual safety of various hormonal and nonhormonal regimens in appropriate patient populations, not in study cohorts artificially created to facilitate a study that does not evaluate the typical patient population that would use the therapeutic intervention. This fact has continued to hamper the development and use of a wide variety of menopausal therapeutic interventions, most notably those containing sex steroids. Nonetheless, new menopausal therapies are being developed and introduced for use by the expanding population of symptomatic postmenopausal women, as demonstrated by the recent Food and Drug Administration approval (in October 2013) of

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the combination of conjugated estrogens and bazedoxifene for the treatment of moderate to severe vasomotor symptoms and for the prevention of osteoporosis.10 Commitment to the health of postmenopausal women requires the availability of safe and reliable interventions, as well as requisite knowledge of the safety, tolerability, and effectiveness of those regimens. The study by Archer et al1 is an integral part of this process and is an indication that the care of postmenopausal women is once again Bon the radar[ of the industry and organizations supporting biomedical research, which can only further improve the health and well being of the increasing number of women living an increasingly greater percentage of their lives after the menopausal transition. Financial disclosure/conflicts of interest: L.P.S. is a consultant to Agile, Bayer, Merck, Shionogi, Teva, Warner-Chilcott, Pfizer Pharmaceuticals, Watson Pharmaceuticals, Sequenom Laboratories, and Natera Laboratories.

Lee P. Shulman, MD Division of Clinical Genetics Department of Obstetrics and Gynecology The Feinberg School of Medicine of Northwestern University Chicago, Illinois REFERENCES 1. Archer DF, Schmelter T, Schaefers M, Gerlinger C, Gude K. A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17A-estradiol for moderate to severe vasomotor symptoms in postmenopausal women. Menopause 2014;21:227-235. 2. 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;288:321-333. 3. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305: 1305-1314. 4. Laliberte´ 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;18:1052-1059. 5. Espen Gjelsvik B, Straand J, Hunskaar S, Dalen I, Rosvold EO. Use and discontinued use of menopausal hormone therapy by healthy women in Norway: the Hordaland Women’s Cohort study [published online ahead of print August 26, 2013]. Menopause 2013. doi: 10.1097/ GME.0b013e3182a11f2d. 6. Shams T, Firwana B, Habib F, et al. SSRIs for hot flashes: a systematic review and meta-analysis of randomized trials. J Gen Intern Med 2013; 29:204-213. 7. Geller SE, Shulman LP, van Breemen RB, et al. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause 2009;16:1156-1166. 8. Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med 2014;174:25-31 9. The North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19:257-271. 10. Mirkin S, Ryan KA, Chandran AB, Komm BS. Bazedoxifene/conjugated estrogens for managing the burden of estrogen deficiency symptoms. Maturitas 2014;77:24-31.

* 2014 The North American Menopause Society

Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.

Has the pendulum begun to swing back?

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