Benefits and risks of postmenopausal hormone therapy: Two expert opinions

September 8, 2014

The initial findings from the WHI were concerning, but subsequent detailed analysis and long-term follow-up of women enrolled in these trials have brought perspective.

New options and additional information add perspective

 

By Hugh S. Taylor, MD

Dr. Taylor is the Anita O'Keeffe Young Professor and Chair, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.

He reports receiving consulting fees from AbbVie, Bayer, and Pfizer, and performing contracted research for AbbVie and Pfizer.

 

Judicious use of therapies for treatment of menopausal symptoms has been a topic of debate for more than a decade. Many concerns about hormone therapy (HT) arose from interpretation of results of the Women’s Health Initiative (WHI), a large, prospective, randomized clinical trial (RCT) that evaluated use of menopausal HT and helped to define its risks and benefits. The initial findings from the WHI were concerning, but subsequent detailed analysis and long-term follow-up of women enrolled in these trials have brought perspective. Moreover, new prospective RCTs have shed more light on appropriate use and safety of HT. Finally, several novel FDA-approved therapies for treatment of menopausal symptoms address many concerns. These therapies offer exciting new options for women suffering from menopausal symptoms. 

The WHI results astounded the media and the public. Some of the purported benefits of HT were not seen in the population treated, while the risks were initially thought to be similar to or greater than those previously reported.1 Most prescribers treat women who are newly menopausal and rarely treat women in the seventh and eighth decades of life, as was done in the WHI.

While media reports typically lumped together therapies composed of estrogens or estrogens given concomitantly with progestins, we have come to learn that the risks and benefits of these therapies are distinct. The combination estrogen and progestin in the WHI studies did not decrease the risk of cardiovascular disease (CVD); in fact, the risk of CVD and stroke was increased in older women using combination HT.1 Reports on the WHI data eventually clarified that use of estrogen alone was not associated with increased risk in the 50- to 59-year-old age group.2,3 In fact, many CVD outcomes were improved in women using conjugated equine estrogens (CEE) alone.4 Further, coronary calcium, a surrogate marker of atherosclerosis, was significantly reduced in the younger women who used CEE alone. This finding suggests that the development of CVD was indeed reduced in newly menopausal women after hysterectomy who were using unopposed estrogen.

Although the risks for both combination and estrogen-based therapies increased with age, current data from the WHI suggest that these therapies can be safely administered without increased risk in women in and around the menopausal transition.5 Further, the use of CEE alone in women who have undergone hysterectomy may have some cardiovascular benefits before age 60.3,6

 

 

More recent prospective RCTs have confirmed the safety of combination HT in newly menopausal women; the Kronos Early Prevention Study showed no evidence of coronary artery calcium deposition or worsening of progression of coronary artery atherosclerosis when combination HT was used in newly menopausal women for 4 years.7,8 Taken together, these studies show that in younger patients typically treated for menopausal symptoms, CVD is not increased by menopausal HT and there may be real cardiovascular benefits with the use of unopposed estrogen.

Other findings from the WHI were not surprising. HT reduced the risk of fracture and HT is known to improve vasomotor symptoms (VMS) and relieve vulvovaginal atrophy (VVA). For many women in the menopausal transition, HT will provide tremendous quality-of-life benefits.

The primary concern of patients and physicians is the potential for increasing the risk of breast cancer with HT.9,10 The WHI results clearly show that combination HT increases the risk of breast cancer.11 Subsequent studies showed that not only was this risk increased, there was also an accompanying increase in breast cancer mortality. These findings overturned the misconception that only less aggressive, non-fatal tumors would be stimulated by hormones.

The risk of breast cancer with traditional combination HT is low and comparable to the risk of automobile fatality that driving creates, a risk that we assume for the convenience it provides.

More importantly, the WHI has shown us the clear distinction between combination HT and estrogen-alone therapies in impact on risk of breast cancer. In women who have undergone hysterectomy and used estrogen alone, the long-term WHI post-treatment intervention follow-up showed a marked reduction in breast cancer among women who used CEE. Contrary to popular misconceptions, estrogens and progestins are distinct hormones with different effects on the breast. For a well-informed woman who has had a hysterectomy and is not at risk of venous thromboembolism (VTE), the decision to use HT should be an easy one.

 

 

New HT options

For women who have not undergone hysterectomy and require a progestin for protection against endometrial cancer, several new alternatives to traditional combination HT are available with greater safety and minimal side effects.

New products include paroxetine, an antidepressant, for reduction in VMS.12,13 It does not have the same level of efficacy as traditional menopausal HT, but paroxetine provides relief for women who want a non-hormone-based alternative.

Selective estrogen receptor modulators (SERMs), which have tissue-specific selective targeting through the estrogen receptor (ER), also have potential in treatment of menopausal symptoms. Raloxifene, a SERM approved for prevention and treatment of osteoporosis, effectively targets ERs in bone while not stimulating those in breasts.14,15 Like many SERMs, it has an antagonistic hormone effect on breasts, reducing the risk of breast cancer.16

Because raloxifene does not effectively provide an estrogen-like effect in the central nervous system and may increase the incidence and severity of VMS. However, other SERMs that may offer benefits have been introduced. Ospemifene, an oral SERM that targets the vagina, provides relief from vaginal atrophy without stimulating the endometrium.17 VVA can be targeted through the oral or vaginal route. This decision includes balancing the risks of systemic therapy (eg, VTE) with the convenience of oral administration.

Perhaps the most innovative and novel therapy to be approved in the United States is the first tissue-selective estrogen complex-a combination of CEE and the SERM bazedoxifene (BZA).18,19 BZA’s unique properties allow it to be specifically coupled with estrogens without the need for a progestin. Its tissue-specific selectivity antagonizes estrogen action on the breast and uterus, but does not effectively counteract the benefits of estrogen on the brain or bone.

Replacing a progestin with a SERM is expected to result in a much more favorable risk profile than combination HT.20 Clinical trials of CEE/BZA have shown effective relief of VMS and improved bone density.21-24 Remarkably, the combination of CEE and BZA produced bleeding rates comparable to placebo, far less than traditionally noted with any estrogen and progestin combination HT.25 Further, it does not increase breast tenderness as was seen with estrogen and progestin.

Mammograms obtained in women using CEE/BZA in clinical trials showed no increase in mammographic density, which is in contrast to the increase seen with combination HT.26

 

 

Summary

More than a decade after the first WHI results, detailed follow-up analysis has revealed a clearer picture of the actual benefits and risks of menopausal HT. Many of the risks that led women to reject therapies for VMS have finally been put into perspective. The distinctive risks of CEE alone versus combination therapy are now unambiguous. The important effect of age has also become apparent. Newly menopausal women can feel confident that they have a full and accurate assessment of the risks and benefits of HT. The reduction in breast cancer risks with use of CEE alone is still underappreciated, but important to our patients to relieve their fears and enable them to make more informed decisions.

Finally, several new products have become available, offering more options and potentially greater safety. Nonhormonal and tissue-specific hormonal therapies have been added to our armamentarium. Perhaps the most promising therapy for women with a uterus is CEE/BZA.

A renaissance in treatment of menopausal symptoms has begun. We are better informed than ever about the side effects and risks of HT and armed with new options. It is time to reengage and inform our patients; we can help them to make knowledgeable decisions.

 

References

1. Manson JE, Hsia J, Johnson KC, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523–534.

2. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–1712.

3. 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(13):1465–1477.

4. Manson JE, Allison MA, Rossouw JE, et al; WHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356(25):2591–2602.

5. Taylor HS, Manson JE. Update in hormone therapy use in menopause. J Clin Endocrinol Metab. 2011;96(2):255-264.

6. Harman SM, Vittinghoff E, Brinton EA, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med. 2011;124(3):199–205.

7. Miller VM, Black DM, Brinton EA, et al. Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J Cardiovasc Transl Res. 2009;2(3):228–239.

8. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014 [Epub ahead of print]

9. Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated equine estrogens and breast cancer risk in the Women’s Health Initiative clinical trial and observational study. Am J Epidemiol. 2008;167(12):1407–1415.

10. Stefanick ML, Anderson GL, Margolis KL, et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647–1657.

11. Chlebowski RT, Kuller LH, Prentice RL, et al; WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573–587.

12. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289(21):2827–2834.

13. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013; 20(10):1027–1035.

14. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997;337(23):1641–1647.

15. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282(7):637–645.

16. Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727–2741.

17. Bachmann GA, Komi JO; Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010;17(3):480–486.

18. Komm BS. A new approach to menopausal therapy: the tissue selective estrogen complex. Reprod Sci. 2008;15(10):984–992.

19 . Kharode Y, Bodine PV, Miller CP, Lyttle CR, Komm BS. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology 2008;149(12):6084–6091.

20. Taylor HS, Ohleth K. Using bazedoxifene plus conjugated estrogens for treating postmenopausal women: a comprehensive review. Menopause. 2012;19(4):479–485.

21. Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial. J Clin Endocrinol Metab. 2014;99(2):E189–98.

22. Pinkerton JV, Abraham L, Bushmakin AG, et al. Evaluation of the efficacy and safety of bazedoxifene/conjugated estrogens for secondary outcomes including vasomotor symptoms in postmenopausal women by years since menopause in the Selective estrogens, Menopause and Response to Therapy (SMART) trials. J Womens Health. 2014;23(1):18–28.

23. Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92(3):1045–1052.

24. Pinkerton JV, Utian WH, Constantine GD, Olivier S, Pickar JH. Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial. Menopause. 2009;16(6):1116–1124.

25. Archer DF, Lewis V, Carr BR, Olivier S, Pickar JH. Bazedoxifene/conjugated estrogens (BZA/CE): incidence of uterine bleeding in postmenopausal women. Fertil Steril. 2009;92(3):1039–1044.

26. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20(2):138–145.

 

NEXT: Dr. Holly Thacker's opinion >>

 

 

Hormone therapy is safe and beneficial when used appropriately

By Holly L. Thacker, MD, FACP, CCD, NCMP

Dr. Thacker is Professor and Chair, Center for Specialized Women’s Health, OB-GYN and Women’s Health Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio. 

She reports receiving salary/honoraria from Pfizer, Shionogi, and Amgen.

 

This is an ideal time to review the benefits and risks of hormone therapy (HT) in menopause, in light of the recent publication of the Women’s Health Initiative (WHI) outcomes, ACOG’s Practice Bulletin update on the management of menopausal symptoms, and recent research documenting that ob/gyn residents have inadequate experience and exposure to menopausal medicine.1-3 In the last year, the FDA has approved 2 nonhormonal therapies for treatment of menopausal symptoms: an oral therapy (a selective estrogen receptor modulator [SERM] also called an oral estrogen agonist/antagonist with tissue-selective effects) for moderate to severe dyspareunia caused by menopausal vulvovaginal atrophy (VVA) and a low-dose oral selective serotonin reuptake inhibitor (SSRI) for the treatment of moderate to severe vasomotor symptoms (VMS) that comes without the psychiatric labeling of other SSRIs.

Systemic HT-with just estrogen (in women without a uterus) or estrogen plus progestin (in women with a uterus)-remains the most effective therapy for treating menopausal VMS.2 Clinicians should individualize care and use the lowest effective dose consistent with the indication for therapy, which does not necessarily imply a limit to therapy. The most important data point in the WHI long-term health outcomes is reduced all-cause mortality with both estrogen alone (in women without a uterus) and combination HT (in women with a uterus) compared to placebo in women within 10 years of menopause who used therapy for more than 5 years.

The benefit of estrogen was mathematically and strikingly demonstrated in a recent analysis that suggested up to 90,000 deaths may have occurred due to post-WHI withholding of estrogen therapy.4

For some time, Dr. Wulf Utian (the founder of both the International Menopause Society and the North American Menopause Society) has called for an independent commission to re-evaluate the WHI investigators’ reports.5 It is up to all women’s health practitioners and educators to educate our patients and our trainees about menopause and menopausal HT. The Study of Women Across the Nation revealed that the productivity of menopausal women suffers if their symptoms are not treated.6 Economic stability is an important component of health and wellness.

 

 

In my opinion, the long-term outcomes of the WHI as well as the Danish Osteoporosis Prevention Study7 swing the pendulum back from using menopausal HT as limited treatment in women severely affected by menopausal hormone deficiency only to using it for primary prevention based on mortality reduction, including bone protection and reduction of cardiovascular disease (CVD).

Hodis and Mack compare the risks of HT with other commonly used medicines.8 They note that data from randomized clinical trials are very reassuring in that risks associated with HT are rare (fewer than 1 event per 1000 women treated) and even rarer in women who initiate HT within 10 years of menopause. Strikingly, HT reduces CVD and total mortality (while aspirin and statins in women treated for primary cardiovascular prevention do not).9

The major risk with the use of HT is venous thromboembolism (VTE). Some have postulated that the use of transdermal estradiol and oral micronized progesterone may reduce the risk of VTE and breast cancer, respectively.10 With respect to breast cancer, oral conjugated equine estrogen (CEE) used for 11 years in the estrogen-only arm of the WHI was not associated with any increase in breast cancer diagnosis, and in adherent women, was associated with a decrease in breast cancer diagnosis.

Because of miscommunication of the results of the WHI, many women turned to unregulated compounded so-called bio-identical hormone therapy (BHT). BHT in the compounded form typically is used in transdermal progesterone cream, which does not achieve high-enough serum levels to reliably protect the endometrium.11

Assessing for relief of menopausal symptoms, visually inspecting for resolution of VVA, and assessing bone density are indirect tissue-level assays of estrogen adequacy.11 Women requesting BHT can be prescribed regulated oral progesterone and oral or transdermal or vaginal estradiol. These products are FDA-approved, commercially available, and do not have to be compounded for most women. The table below describes options for delivering HT.

In general, estrogen alone is used in cases of hysterectomy and progestin is used either continuously with the goal of amenorrhea within 6 months or cycled for 12 days each month. Testosterone is not FDA-approved and therefore not standard of care in the United States. However, for women with androgen deficiency, one generic oral esterified estrogen with oral methyl-testosterone combination is available. It can also be considered, along with off-label compounded topical testosterone, for women who have undergone hysterectomy with oophorectomy and have persistent VMS on estrogen alone, but that should be done carefully to avoid supra-physiologic levels.12

Pellets of estrogen, progesterone, and testosterone are not FDA-approved and are not recommended. Data do not support the use of progestin alone, testosterone alone, compounded BHT, phytoestrogens, herbal supplements, and/or lifestyle modifications to treat menopausal VMS.2

 

Benefits of HT include relief of VMS (which can include hot flashes, night sweats, and rarely formication, which is a sense of something crawling on the body) and treatment of VVA. If VVA is the only menopausal symptom, local estrogen or the new non-hormonal ospemifene should be considered.13 The major risk with this systemic SERM is the risk of VTE.

Local estrogens are available in 2 creams, 1 vaginal ring and 1 vaginal tablet. Some women prefer oral therapy to local vaginal therapy and may be candidates for systemic HT or oral ospemifene alone.

The only nonhormonal agent approved to treat VMS is low-dose paroxetine, which has shown statistical significance at week 4 and week 12 with persistence of benefit of treating VMS at week 24.14 Coadministration of paroxetine can alter concentrations of other drugs such as tamoxifen. The lower doses of paroxetine do not appear to be associated with weight gain and sexual dysfunction.

Many other SSRI and norepinephrine serotonin reuptake inhibitors (NSRI) have been studied, although only low-dose paroxetine is FDA-approved. Choosing an appropriate therapy requires careful assessment of the risk-benefit as well patient preference and comorbid medical conditions.15

Other benefits associated with HT use include reduction in type 2 diabetes, colon cancer, and fracture and improvement in minor mood and neurocognitive symptoms associated with sleep deprivation from VMS. Estrogen also may benefit skin and hair among women who are estrogen-deficient but who have endogenous levels of androgens promoting hair thinning and acne, and in some women, even a deepening of the upper register of the voice. Risks besides VTE and invasive breast cancer (with long-term combination HT) include a higher incidence of all cardiovascular events, gall bladder disease, and probable dementia.1 Among the nuisance side effects are breast tenderness and uterine bleeding.

Endometrial hyperplasia and endometrial cancer are associated with unopposed estrogen use. Oral estrogen can be associated with increase in blood pressure in some women and elevated triglyceride levels and gallstones. Fluctuating hormone levels can affect migraine headaches. Women with seizure disorders need adequate progestin therapy as estrogen can lower the seizure threshold.

Several societies, including the international Menopause Society and the Endocrine Society, have issued helpful guidelines.2,16,17 The North American Menopause Society’s most recent position admits that the data support the initiation of HT around the time of menopause to treat symptoms and to prevent osteoporosis in women at high risk of fracture.18 Risks of stroke, dementia, and myocardial infarction are highest in women initiating therapy several decades from menopause.

 

 

Menopause is a potential endocrinopathy. If a patient has premature menopause or early menopause, pressing long-term consequences of hormone deficiency include premature death, CV disease, osteoporosis, sexual dysfunction, and neuropsychiatric problems.19 Many women produce enough steroid hormones to be free of symptoms or to experience only asymptomatic bone loss and later-onset VVA. Some women will never experience VMS even with castration. However, half of all women have VMS, and for some they last for decades. Half of all women experience an osteoporotic fracture in their lifetime, which is generally related to estrogen deficiency. A vast majority experience VVA, which may not be symptomatic, but if it progresses and/or is not treated, can lead to structural changes in the vagina, vulva, trigone of the bladder, and urethra, and elevation in vaginal pH.

Women who have had menopausal-onset neuropsychiatric problems and/or sleep disorders such as insomnia should continue on long-term HT even after their condition has stabilized.

The newest HT approved by the FDA is oral conjugated estrogen plus bazedoxifene (BZA), a SERM. It is approved for treatment of VMS and prevention of osteoporosis.20 BZA replaces the progestin medroxyprogesterone acetate (MPA) in Prempro. BZA has estrogen antagonistic endometrial effects and independent agonistic effects on bone.

Many menopausal women have osteopenia, not osteoporosis, and thus are not candidates for other osteoporosis therapies. Therefore, systemic HT or systemic estrogen plus a SERM like CEE/BVA (or if no VMS and osteopenia or osteoporosis and increased risk of breast cancer then oral daily raloxifene) should be considered. Raloxifene is FDA-approved to prevent and treat osteoporosis and to reduce risk of diagnosis of estrogen receptor (ER)-positive breast cancer. All systemic estrogens and all SERMS  can increase the risk of VTE 2 fold.

Work-up for menopause

When evaluating a woman for menopause, first ascertain whether she is menopausal. Not all amenorrhea is menopause and not all midlife symptoms are menopause. Next, does she have a uterus? If she has had a hysterectomy, is she a candidate for estrogen alone? If she has had a provoked VTE in the past, it is best to consider transdermal HT.17 If she has active ER-positive breast cancer, unstable CVD, or uterine cancer, then non-estrogen alternatives should be considered.

Fear of breast cancer is not a reason to avoid oral estrogen. If she has a uterus/endometrium, then the decision to use progestin cyclically or continuously needs to be made. If she is not a candidate or declines HT, then FDA-approved non-hormonal therapies should be considered. Finally, any woman who was on systemic HT for menopausal symptoms who has stopped and has not had recurrence of VMS needs to be assessed for bone loss and VVA.

 

 

There are several lower-dose HT options.21 I am not a fan of ultra-low-dose systemic HT in otherwise healthy recently menopausal women particularly if it leads to incompletely treated VMS requiring SSRIs or sleep agents, incompletely treated VVA requiring additional local estrogen therapy, and/or bone loss requiring addition of a bone-sparing agent.

However, women over age 60–65 who are stable should be evaluated for a reduction in HT dose. The lowest dose of estrogen that is FDA-approved for women ages 60–80 with T scores between -1.0 and -2.0 is the estradiol transdermal 0.014 weekly patch to prevent osteoporosis. Based on this ultra-low dose of estrogen, a progestin is needed for 12 days only once or twice a year in women with a uterus and has been FDA-approved for the last decade.22

Summary

When evaluating menopausal women for menopausal HT, it is important to look at the totality of the data, review recent position papers by national societies, and individually evaluate your patients.

The pendulum is swinging back to primary prevention with HT. It is up to you to communicate this to your patients and offer the newer FDA-approved non-hormonal options to those for whom they are appropriate.

 

References

1. 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;310:1353–1368.

2. American College of Obstetricians and Gynecologists. Practice Bulletin No. 141. Management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202–216.

3. Christianson MS, Ducie JA, Altman J, et al. Menopause education: needs assessment of American obstetrics and gynecology residents. Menopause. 2013;20:1120–1125.

4. Sarrel PM, et al. The mortality toll of estrogen avoidance: An analysis of excess deaths among hysterectomized women age 50 to 59. Am J Pub Health. 2013;109(9):1583–1588.

5. Utian WH. A decade post WHI, menopausal HT comes full circle-need for an independent commission. Climacteric. 2012;15:320.

6. Tseng LA, El Khoudary SR, Young EA, et al. The association of menopausal status with physical function. The SWAN. Menopause. 2012;19:1186–1192.

7. Shierbeck LL, Renjnmark L, Tofteng CL, et al Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ. 2012;345:e6409.

8. Hodis, H, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 2: comparative risks. J Am Geriatr Soc. 2013;61:1011–1018.

9. Hodis H, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 1: comparison of therapeutic efficacy. J Am Geriatric Soc. 2013;61:1005–1010.

10. Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause. 2014;21:1–15.

11. Pattimakiel L. Thacker HL Bioidentical hormone therapy: Clarifying the misconceptions. CCJM. 2011;78(12):829–836.

12. Thacker HL. The Cleveland Clinic Guide to Menopause. 2009 Kaplan. Chapter 11 Customizing Hormone Therapy pgs 181–200.

13. Portman DJ, Bachman GA, Simon JA, and the Ospemifene Study Group. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20:623–630.

14. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013;20(10):1027–1035.

15. Thacker HL. Assessing risks and benefits of nonhormonal treatments for vasomotor symptoms in perimenopausal and postmenopausal women. J WH. 2011;20:1007–1016.

16. Sturdee DW, Pines A. International Menopause Society Writing Group, et al. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. Climacteric. 2011;14:302–320.

17. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95:s1–s66.

18. The 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 2012;19:257–271.

19. Shuster LT, Rhodes J, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas. 2010;65(2):161.

20. Tella SH, Gallagher JC. Bazedoxifene + conjugated estrogens in HT for the prevention of osteoporosis and treatment of vasomotor symptoms associated with the menopause. Expert Opin Pharmacother. 2013;14:2407–2420.

21. Sivandandy MS, Masimasi N, Thacker HL. Newer hormonal therapies: Lower doses: oral, transdermal, and vaginal formulations. CCJM. 2007;74:369–374.

22. 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;104:443–451.