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Central Journal of Endocrinology, Diabetes & Obesity

Review Article Corresponding authors Orkun Tan, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology Hormonal and Non-Hormonal and , University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390 and ReproMed Center, 3800 San Management of Vasomotor Jacinto Dallas, TX 75204, USA, Tel: 214-648-4747; Fax: 214-648-8066; E-mail: [email protected] Submitted: 07 September 2013 Symptoms: A Narrated Review Accepted: 05 October 2013 Orkun Tan1,2*, Anil Pinto2 and Bruce R. Carr1 Published: 07 October 2013 1Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology Copyright and Infertility, University of Texas Southwestern Medical Center, USA © 2013 Tan et al. 2Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, ReproMed Fertility Center, USA OPEN ACCESS

Abstract Background: Vasomotor symptoms (VMS; hot flashes, hot flushes) are the most common complaints of peri- and postmenopausal women. Therapies include various and - combinations. However, both physicians and patients became concerned about -related therapies following publication of data by the Women’s Health Initiative (WHI) study and have turned to non-hormonal approaches of varying effectiveness and risks. Objective: Comparison of the efficacy of non-hormonal VMS therapies with estrogen replacement therapy (ERT) or ERT combined with progestogen (Menopausal Hormone Treatment; MHT) and the development of literature-based guidelines for the use of hormonal and non-hormonal VMS therapies. Methods: Pubmed, Cochrane Controlled Clinical Trials Register Database and Scopus were searched for relevant clinical trials that provided data on the treatment of VMS up to June 2013. Findings: Depending on the dose, ERT using any of several types of (ER) ligands is unequivocally the most effective treatment for VMS. In most studies, the selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), , and gabapentin are more effective than placebo. Paroxetine, which is an SSRI, is the only FDA-approved non-hormonal agent for the treatment of VMS. SSRIs must be used with caution in women with breast receiving adjuvant therapy since SSRIs reduce the of tamoxifen to its most active metabolite, . Although gabapentin and some of the SNRIs may be effective in relieving VMS, there are safety concerns with their use such as increased risk of suicidal thoughts with gabapentin and hepatotoxicity and increased rate of cardiovascular events with desvenlafaxine. Oral micronized is effective for treatment of VMS in early postmenopausal women. /conjugated estrogen may be a promising alternative to for the treatment of VMS. The effects of on VMS are similar to placebo. Black cohoshes, dong quai, evening primrose oil, ginseng extract, kava kava, vitamin E, red clover leaf, hypnosis, acupuncture are either ineffective or not clinically significantly efficacious in the treatment of VMS. Conclusions: VMS vary greatly in severity, and women with mild to moderate symptoms may not need to use ERT/MHT, or any treatment at all. However if used, ERT or MHT is effective for the treatment of VMS. Initial one to three month trials for efficacy and tolerance are recommended since relief from VMS is usually substantial within 4 weeks of starting ERT/MHT. As with all treatments, the risks and benefits of estrogen treatments and neurotransmitter- active treatments must be reviewed before they are administered. Randomized double blind controlled trials comparing paroxetine, SNRIs, clonidine, dehydroepiandrostenedione or stellate ganglion block with ERT/MHT are needed to confirm their efficacy and profiles. So-called “bioidenticals” have no advantage over conventional preparations and are not subject to FDA standards.

INTRODUCTION In menopausal women, vasomotor symptoms (VMS; hot reviewEvaluation of the presentof VMS state of treatment for VMS was needed. flashes, hot flushes) are due to decreased estrogen and they There is no need for diagnostic studies in peri- and post- are described as waves of feeling hot then cold and sweating, menopausal women who are suffering from VMS unless they primarily over the “shield area” of the anterior body surfaces [1]. do not respond to estrogen or have additional symptoms VMS occur in conjunction with decreased estrogen levels/action consistent with infection, hyperthyroidism, narcotic withdrawal, in women and usually their severity and frequency mirrors the pheochromocytoma, consumption, carcinoid syndrome, abruptness of the loss of estrogen activity [2,3]. dumping syndrome, and such as nitrates, , It was for decades the approach to offer FDA- (Food and Drug -releasing hormone , and anti-estrogens Administration) approved estrogen combined with progestogen (see Figure 1 “Useful Tips”). Levels of follicle-stimulating (Menopausal Hormone Treatment, MHT) for menopausal VMS. hormone and may be within the normal The Women’s Health Initiative study (WHI) drove most women premenopausalTreatment of rangemenopausal during the VMS menopausal transition [6]. and their caregivers away from MHT, including its use for VMS Placebo effect [4]. As a result menopausal women have turned to other, non- hormonal means of relieving VMS [5]. Therefore, a comprehensive : Evaluation of the treatment of VMS is Cite this article: Tan O, Pinto A, Carr BR (2013) Hormonal and Non-Hormonal Management of Vasomotor Symptoms: A Narrated Review. J Endocrinol Dia- betes Obes 1(2): 1009. Tan et al. (2013) Email: [email protected] Central

Standard Dose Estrogen Therapy Low Dose Estrogen Therapy complicated by a strong placebo effect [7]. The following • Oral Conjugated Estrogen (CE; Premarin): 0.625 • Oral CE: 0.45 mg/d, 0.3 mg/d mg/d • Oral 17-β : 0.5 mg/d, 0.25 mg/d discussion takes the placebo effect into account by specifying • Oral 17-β Estradiol (Estrace): 1 mg/d, 2 mg/d • Transdermal 17-β Estradiol: 25 mcg patch/wk • Transdermal 17-β Estradiol (Climara): (50-100 mcg whether long-term, placebo-controlled trials are considered. patch)/wk • Microdose Transdermal Estrogen Therapy: 17β- • (Estradiol ; *Femring estradiol, 0.014 mg/day Randomized controlled prospective, single- or double-blinded ): 0.05-0.1 mg/every 90 days trials comparing the efficacy of hormonal or nonhormonal options with the gold standard ERT or MHT for the relief of VMS wereHormonal also included treatment in this ofreview. VMS Estrogen-Progestogen Combinations Oral continuousa: (CE) and (MPA), Estrogen plus Progestogen replacement therapy (MHT): • acetate (MPA): 2,5-5-10 mg/d • 0.625 CE and 2.5 or 5 mg MPA • acetate: 20, 40, 80 mg/d • 0.3 or 0.45 CE and 1.5 mg MPA • Oral micronized progesterone: Prometrium 100, 200 • Low dose: 0.5 mg 17β-estradiol and 0.1 mg mg/d acetate • Oral Sequentialb: 0.625 mg CE and 5 mg MPA • Transdermal continuous: Until recently, see above, MHT was the most common treatment • 1 mg 17-β Estradiol plus 5 mg Norethindrone for VMS. A systematic review and meta-analysis of 32 treatment • 0.05 mg 17-β Estradiol plus 0.015 mg trials found that the use of conjugated equine estrogens (CEE), oral or transdermal 17β-estradiol alone has consistent and Figure 2 comparable effects on the treatment of VMS in menopausal Selected Hormonal Treatment Options for Relief of VMS. women. All estrogen agents significantly reduced the weekly *Femring delivers a high systemic level of estrogen and should be opposed by a number of VMS compared with placebo (CEE, 1 trial: mean progestogen in women with a uterus. a Continuous means throughout the month. change, –19.1; oral 17β-estradiol, 5 trials: pooled weighted mean b Sequential means estrogen alone is followed by estrogen and progesterone. difference, –16.8; transdermal 17β-estradiol, 6 trials: pooled d: day, wk: week weighted mean difference, –22.4) and differences between agents were not significant [8]. A 2009 Cochrane meta-analysis randomized trial examined the efficacy and safety of low doses of including 24 trials found that ERT or MHT greatly reduces the combined with MPA and found that lower frequency and severity of VMS compared to placebo. VMS doses relieved vasomotor symptoms as effectively as standard frequency was reduced 75%, and severity decreased as well [9]. doses [12]. Doses of conjugated estrogens at 0.45 and 0.3 mg/d, There are many MHT preparations with different regimens, with and without concurrent MPA, significantly reduced the routes of administration, and doses (see Figure 2). Currently frequency and severity of VMS compared with placebo by the there is no evidence indicating that one product is superior to third week of treatment. There were no significant differences another for relief of VMS. Because of the risk of endometrial regarding the relief of VMS between conjugated estrogens (0.625 hyperplasia and endometrial adenocarcinoma with prolonged mg) plus MPA (2.5 mg) and any of the lower-dosage conjugated unopposed estrogen use, all women with an intact uterus estrogens (0.3 and 0.45 mg) plus MPA groups (1.5 mg), although should receive systemic progestogen with estrogen [10]. Relief low-dose conjugated estrogen without MPA was not quite as from the frequency and severity of VMS is usually substantial effective as standard-dose conjugated estrogens (0.625 mg) or within 4 weeks after starting standard doses (0.625 mg) of low-dose conjugated estrogens/Medroxyprogesterone acetate estrogens (See Figure 2). An oral of CEE 0.625 mg/ combinations. This may be because Medroxyprogesterone day with Medroxyprogesterone acetate (MPA) is the most acetate has an independent effect on VMS reduction [7,13]. commonly used MHT in menopausal hot flashes trials. It has been Levonorgestrel-containing (LnG- demonstrated that VMS were reduced by 83% using standard- IUD; Mirena, Bayer HealthCare Pharmaceuticals Inc., USA) is dose conjugated estrogens (0.625 mg) and by 63% with low-dose approved by FDA for contraception and the treatment of heavy conjugated estrogens (0.3, 0.45 mg) [11]. Lower doses may not menstrual bleeding for women who choose to use intrauterine have maximal effects for 8 to 12 weeks but are associated with contraception as their method of contraception. However LnG- fewer side effects, such as breast tenderness [11]. A double blind, IUD which delivers 20 µg of levonorgestrel over a 24-hour period is now licensed for use as the progestogen component of In persistent VMS cases, rule out other potential causes Estrogen Replacement Treatment (ERT): (hyperthyroidism, pheochromocytoma, alcohol use, continuous estrogen therapy in [14]. infections such as tuberculosis, malignancies such as lymphoma, medications such as nitrates, niacin) Estrogen alone markedly improves the frequency and severity of VMS as demonstrated by many randomized trials [8]. Estrogens, which Tapering of hormone therapy rather than stopping are available in oral, transdermal, vaginal ring and topical forms, abruptly may be preferred if discontinuation is desired in patients with history of severe VMS are effective in up to 90% of women with VMS (see Figure 2) [15]. The benefit is dose-related and even low doses of estrogens are Given the natural history of VMS, it is reasonable to try often effective [12,16,17]. With standard doses of estrogens (CEE, discontinuing hormone therapy every 12 months. If 0.625 mg; oral micronized 17β-estradiol, 1 mg; transdermal symptoms recur, restarting and then gradually tapering 17β-estradiol, 50 μg/d), relief from VMS is usually seen within the dose or the number of days per week that 1 month [18]. Lower doses may not have maximal effects for 2-3 are used may be helpful months but side effects such as breast tenderness and uterine Figure 1 bleeding are less commonly seen compared to the higher doses [11,18]. Examples for lower doses of estrogens include CE Useful Tips. (0.3 mg, 0.45 mg), micronized oral 17β-estradiol (0.5 mg), and J Endocrinol Diabetes Obes 1(2): 1009 (2013) 2/15 Tan et al. (2013) Email: [email protected] Central

transdermal 17β-estradiol (0.025 mg). ERT is the standard of among women in certain age groups in the United care for post-hysterectomy patients for the treatment of VMS. States is predominantly related to a decrease in the use of MHT Women without a uterus do not require progestogens. [27]. The endocrine society in 2010 reported that MHT increases the risk of invasive breast cancer, which may occur within 3 to Since the preparations that are presently available for 5 yr of initiation and rises progressively beyond that time [28]. ERT and MHT have been assessed for satisfactory rates of In the same statement, congruent trends suggested additional endometrial- and other complications, we suggest starting benefit including reduction of overall mortality and coronary with an FDA-approved “low dose” regimen by either the oral artery disease in the subgroup of women starting MHT between or parenteral route and assessing the effect on VMS after one to ages 50 and 59 or less than 10 yr after onset of [28]. three months. Some studies have shown that low-dose estrogens may be less likely to cause many of the potential risks associated So far, basic science studies and numerous animal models with higher dose estrogens [19]. If the dose is effective it may provide biological plausibility for the concept that estrogens be continued. However, if the effect is not adequate, higher-dose, can exert atheroprotective effects via both systemic effects FDA-approvedFollow-up formulationsof patients on may MHT/ERT: be tested. on circulating factors and direct effects on the heart and blood vessels [29,30]. Subgroup analyses suggest that the lack of neither the dose nor benefit or increase in CHD risk observed in the overall analysis length of this period is defined, especially in regards to individual of the WHI resulted from harmful effects of MHT in older women patient needs, the length of therapy should be periodically starting therapy many years after onset of menopause [28]. reviewed with the patient. Consideration should include the likelihood that she no longer needs the MHT/ERT for VMS. It is not The results of studies regarding the effects of estrogens on necessary to routinely evaluate the of women with cognition have been conflicting [31,32]. As a possible explanation, uterine spotting or light uterine bleeding in the first six months Henderson and Sherwin suggested that estrogen might have an of continuous MHT (throughout the month) [20]. Endometrial age-dependent neuroprotective effect on the brain [33,34]. They assessment of such women is recommended if spotting or proposed the “critical window” or “timing” hypothesis, which bleeding persists beyond six months, although there is a very low suggests that estrogen begun later in menopause does not benefit incidence of or neoplasia [21]. cognitive outcome and, instead, is detrimental. However, early initiation of estrogen might reduce dementia risk [31,33-35]. ERT/MHT has long-term health risks and benefits. In a 2011 randomized controlled trial (RCT), LaCroix et al. investigated In conclusion, hormone therapy should not be prescribed to health outcomes after stopping conjugated equine estrogens women with a history of breast cancer and should be used by (CEE) among postmenopausal women (between ages 50- women at high risk only after a careful assessment of potential 79) with prior hysterectomy. In the CEE group, at the time of risks and benefits. These findings should be reassuring to hysterectomy, 39.8 % of patients were <40 years of age, 43.7% women and their clinicians considering short-duration HT for between 40-49 years of age, 9.2% between 50-54 years of age bothersome VMS at the time of the menopausal transition. The and 7% ≥ 55 years of age. CEE use for a median of 5.9 years was lowest effective estrogen dose with the shortest duration should not associated with an increased or decreased risk of coronary be given to the patients since the risks increase with increasing heart disease (CHD), deep vein , stroke, hip fracture, age, time since menopause, and duration of use. Women must colorectal cancer, or total mortality [22]. A 2009 meta-analysis be informed of the potential risks and benefits of ERT/MHT, and indicated a reduction in mortality in younger postmenopausal care should be individualized, based on the medical history, risk women (aged 50-59 years) taking hormone therapy compared factorsProgestogens: and expected benefits from hormonal therapy [7]. with no treatment [23]. However ERT/MHT use is not without Different progestogens, such as MPA and significant risks. Contraindications to MHT use include breast have been used effectively for the treatment or , cardiovascular disease, thromboembolic of VMS (see Figure 2). Studies of the efficacy of megestrol acetate disorders, and active disease [7]. Whereas observational for the prevention of VMS have been limited to breast cancer studies and WHI were at odds regarding coronary survivors. In a double blind, placebo-controlled randomized heart disease risk, findings regarding breast cancer were trial, patients receiving megestrol acetate, at a dose of 40 mg extremely consistent. A randomized trial of hormone therapy per day, showed an 85% reduction in VMS, as compared to a use in women with a history of breast cancer and bothersome 21% reduction in the placebo group. In a randomized placebo vasomotor symptoms was terminated early, after 2 years of controlled trial, Goodwin et al. compared megestrol acetate (MA) follow-up, when more new breast cancer events were diagnosed 20 mg or 40 mg with placebo as treatment for VMS over 6 months in women randomly assigned to hormone therapy [24]. Estrogen- in patients with a history of breast cancer [36]. Patients were alone therapy was associated with a significantly increased risk randomly assigned to placebo, MA 20 mg or 40 mg for 3 months. of breast cancer after 15 years of current use in the Nurses’ Success at 3 months was defined as completion of treatment Health Study [25] and for current users in the Million Women with ≥75% reduction in VMS from baseline. Success at 3 months observational study of United Kingdom women [26]. An increased was 14% on placebo, 65% on 20 mg MA, and 48% on 40 mg MA risk of breast cancer is seen after approximately 5 years of MHT [36] concluding that MA with either dose is significantly more use, with no increased risk seen in short-term or past-users [7]. effective than placebo in controlling VMS. In 2009, WHI investigators reported that the increased risk of breast cancer associated with MHT declined markedly soon after Treatment with MPA was reported to control VMS as discontinuation of the therapy suggesting that the incidence of effectively as estrogens in two studies [37]. In one study, 43 J Endocrinol Diabetes Obes 1(2): 1009 (2013) 3/15 Tan et al. (2013) Email: [email protected] Central

women who had undergone a natural (n=8) or surgical menopause receptor modulators. Nachtigall et al. recently investigated (n=35) were randomized to receive either 0.625 mg of CEE or an the effect of on platelet function in 25 symptomatic of 150 mg of depo-medroxyprogesterone postmenopausal women with normal clotting times and seven acetate (DMPA) for 25 days each month [38]. VMS decreased symptomatic women with shortened clotting times (<61 s) significantly in both groups, and this reduction was of a similar [45]. Those women were being treated for severe menopausal magnitude with either treatment after 3 months of therapy. VMS symptoms with Femarelle. All participants reported improved decreased 61.5 ± 7.5% with conjugated estrogens and 69.4 ± symptoms during the treatment period (8 weeks and 1 year 7.7% with DMPA [38]. In the randomized double blind parallel follow up). Femarelle did not adversely affect platelet reactivity, group controlled trial, oral CEE (0.5 mg/day; n=18 patients) and as measured by Platelet Function Analyzer-100 closure times, in MPA (10 mg /day; n=20 patients) were compared for their effects symptomatic thrombophilic postmenopausal women or normal on VMS for duration of 1 year. Their results showed that MPA and controls therefore it may offer a new clinical choice for therapy of CEE were equivalent and effective in the control of the number symptomatic postmenopausal women [45]. of VMS immediately following premenopausal ovariectomy [39]. TSECs are the pairing of estrogen(s) with a selective estrogen Micronized progesterone is molecularly identical to human (SERM). The goal of developing a TSEC is progesterone. A 2012 placebo-controlled randomized clinical to provide the clinical benefits of each of its components with trial compared oral micronized progesterone with placebo for improved . This goal can potentially be achieved the treatment of postmenopausal VMS [40]. Participants (ages by the result of the different molecular and cellular activities between 44 and 62) were randomized to progesterone 300 mg of the treatment’s estrogen and SERM components [46]. Both once a day at bedtime (n = 68) or placebo (n = 46) and followed up estrogens and SERMs bind to estrogen receptors, eliciting a to 12 weeks and they recorded daily frequency and severity (1-4) range of effects in different cell types and exhibiting tissue- dependent estrogen receptor and antagonist activity, of VMS in the Daily Menopause Diary.- The -VMS scores of women both alone and when combined [47-50]. The therapeutic profile -taking progesterone- were better than placebo with mean VMS score reductions of 10.0 (95% CI, 12.0 to 8.1) and 4.4 (95% CI, of a TSEC would optimally include relief of VMS, treatment of 6.6 to 2.2) in the progesterone and placebo arms, respectively. vulvovaginal atrophy and its symptoms, and prevention of bone This study showed that oral micronized progesterone is loss, while providing safety for the endometrium and breast [51]. effective for treatment of VMS in early postmenopausal women Bazedoxifene, a SERM studied for the prevention and treatment [40]. Bioidentical progesterone cream was also studied for the of postmenopausal , [52] paired with conjugated treatment of VMS as compared to the placebo but not to the estrogen (CE) represents a TSEC [46]. gold standard estrogen. Evidence from these studies does not In SMART-2 study, 332 postmenopausal women were support the efficacy of bioidentical progesterone cream for the examined for VMS as a primary endpoint over 12 weeks (with at management of VMS [41]. least 7 moderate-to-severe VMS/day or 50/week). Participants Whereas progesterone use seems to be effective in alleviating received bazedoxifene (BZA) 20 mg/conjugated estrogen (CE) VMS, the risk of breast cancer associated with progesterone 0.45 mg or 0.625 mg or placebo. At weeks 4 and 12, women use needs to be discussed with the patients. The 2010 taking BZA/CE had significant reductions from baselineP in the endocrine society statement reveals that combined estrogen mean daily number and severity of moderate to severe VMS and progesterone therapy increases the risk of invasive breast compared with placebo at 4 and 12 weeks follow up ( < 0.001). cancer, which may occur within 3 to 5 year of initiation and rises The number of VMS was reduced by 74% for BZA 20 mg/CE 0.45 progressively beyond that time [28]. mg and 80% for BZA 20/CE 0.625 mg, whereas it was 51% for placebo and significant decreases in VMS frequency and severity Progesterone use may be associated with some side effects with both BZA/CE doses compared with placebo were sustained such as headache, depression, and irregular bleeding until week 12 [53]. and [42]. The injectable MPA carries a black box warning stating that prolonged use of more than 2 years may Overall BZA/CE may be a promising alternative to cause loss of bone mineral density [42]. Based on the limited hormone therapy for the treatment of menopausal symptoms available data, the use of other forms of progesterone has not and prevention of osteoporosis in non-hysterectomized been associated with any significant loss of bone mineral density postmenopausal women [54]. Bazedoxifene/CE is not FDA Tibolone: [37-43].Selective Estrogen Receptor Modulators (SERMs) and approved yet. Tissue-Selective Estrogen Complexes (TSECs): Tibolone has been commonly used in and for the treatment of vasomotor symptoms, but is not An ideal approved by FDA [55]. In one study, after 12 weeks of treatment, hormone therapy would reduce the number and severity of VMS, around 80% of the women in tibolone group had no or only mild effectively treat vulvovaginal atrophy and its symptoms, prevent VMS, compared to 40% in the placebo group [56]. In 2010, 11 Asia and treat menopausal osteoporosis, and have favorable effects on Pacific countries developed recommendations for its use in Asian lipoprotein profiles, while at the same time would not stimulate postmenopausal women, based on the evidence from clinical the endometrium, not cause uterine bleeding, not increase the studies published since 2005 and the panel agreed that because risk of vascular events, not be associated with or it has specific effects in different tissues after conversion to tenderness, and potentially reduce breast cancer incidence [44]. three active metabolites (estrogenic, androgenic, progestogenic Femarelle (DT56a) is one of the selective estrogen metabolites) following oral ingestion, there was a need for data J Endocrinol Diabetes Obes 1(2): 1009 (2013) 4/15 Tan et al. (2013) Email: [email protected] Central

on the possible adverse effects of tibolone on the cardiovascular phytoestrogens use is limited, and long-term side effects have system and endometrial cancer in treatment patients [57]. In not been well investigated [18]. Women using these estrogen addition tibolone has been shown to increase the risk of stroke receptor-active compounds should be followed in the same by two-fold in older women with osteoporosis [58]. Although the manner as women using ERT/MHT [62]. A Cochrane meta 2010 endocrine society scientific statement reported tibolone as analysis included 30 RCTs investigating the efficacy of dietary an effective agent in alleviating VMS (level of evidence A), it has soy, soy extracts, and red clover extracts (promensil) in the been associated with an increased risk of stroke in older women treatment of VMS [69]. There was no evidence of a difference [28] and tibolone increases the risk of breast cancer recurrence in in percentage reduction in VMS between study groups and breast cancer survivors [59]. In a 2013 study, authors compared placebo. There was a strong placebo effect in most trial with a the effects of a continuous-combined regimen of low-dose reduction in frequency ranging from 1% to 59% with placebo. hormone therapy versus tibolone and supplemental / Although some of the individual studies in the meta analysis vitamin D3 (control) on quality of life in postmenopausal women found that treatments alleviated the frequency with VMS. The patients were randomised into three groups: (a) and severity of VMS when compared to placebo but most of daily treatment with 2.5 mg tibolone (n = 64), (b) 50 mg calcium these studies were of low quality and were underpowered [69]. carbonate + 200 IU vitamin D3 (Ca/Vit D3, n = 54) or (c) 1 mg In a single-center, 6-month, randomized, double blind, estrogen- estradiol + 0.5 mg norethindrone acetate (n = 56) for 12 weeks. controlled trial, Kaari et al. evaluated the effects of Low dose hormone therapy was superior to tibolone and Ca/Vit on the climacteric symptoms in addition to other parameters in D3 treatment for improvements in vasomotor symptoms [60]. postmenopausal women. Seventy-nine women were randomly assigned to one of the two treatment groups: isoflavone (n=40) A 2012 Cochrane review by Formoso et al. investigated the 300 mg of the standardized soy extract with a medium dose of efficacy as well as short and long term effects of tibolone in 120 mg /day as glycoside and aglycone (60 mg twice postmenopausal women and concluded that there was evidence a day), or estrogen (n=39) one capsule of 0.625 mg CEE and other that treatment with combined HT is more effective in managing capsule with glucose 0.625 mg (placebo). After one month, there menopausal symptoms than with tibolone. Long-term safety of was a significant decrease in VMS. There was a decrease in the tibolone is concerning given the increase risk of stroke in women VMS (total score) of 2.8 times (p<0.01 compared to baseline) whose mean age is over 60 [61]. Currently, due to safety concerns in estrogen group and 1.8 times (p<0.01 compared to baseline) with tibolone, it should not be used in the postmenopausal in isoflavone group. There was also a significant improvement womenDehydroepiandrosterone [62]. Tibolone is not FDA-approved.: It in VMS after the second month of treatment in the isoflavones group compared to the first month (p<0.05). Authors concluded (DHEA) is a pro-hormone produced by the adrenal glands. that the daily standardized soy extract with 120 mg isoflavones’ furnishes both estrogens and . DHEA levels decrease effect on symptoms was similar to that from estrogen [72]. In a following puberty. The circulating DHEA decreases dramatically recent 2010 meta analysis including 19 studies, Bolanos et al. during the perimenopausal period [62,63]. A prospective pilot investigated whether intervention with soy (dietary, extract, or trial was performed in 22 women and found a decrease in mean concentrate), as compared with placebo, reduces the incidence of VMS scores of 50% and an improvement in quality of life related VMS in climacteric women [73]. Although the overall combined to VMS after 4 weeks of DHEA therapy [63]. Currently, there are results and the results by subgroups (according to the type no double blind RCTs comparing DHEA with ERT/MHT therefore of supplement used) showed a significant tendency in favor of its safetyIsoflavones and efficacy is and limited in the other treatment phytoestrogens of VMS. : soy, authors could not establish conclusive results given the high heterogeneity found in the studies [73]. Although one We randomized double blind estrogen controlled trial showed that Phytoestrogens include compounds that contain one or more soy extract with 120 mg isoflavones’ effect on VMS was effective phenolic rings (isoflavones, , coumestanes) [64]. and similar to estrogen [72], most of the trials are small, of separate the discussion of the use of phytoestrogens from short duration and poor quality [69]. Some trials found a slight botanicals because the phytoestrogens preparations available reduction in VMS with phytoestrogen-based treatment [69] in the US are extracts subjected to manufacturing standards but overall there is no strong evidence that phytoestrogens are that offer high likelihood of reproducibility compared to other more effective than placebo. In 2012, Eden et al. performed a botanical products. Phytoestrogens are rapidly and extensively systematic literature review and concluded that although the metabolized in the body, making identification of active efficacy of isoflavones are slightly superior than placebo in some compounds difficult; however, the active phytoestrogens and studies, the magnitute of effect is so small that it is not clinically metabolites bind to ER-α [65] and -β [66] and this is considered significant and overall isoflavones are not clinically superior than to be their [65,67]. A substantial number of placeboNONHORMONAL in the treatment THERAPY of VMS. studies of phytoestrogens and isoflavones have been conducted and have not shown clear benefits over placebo for the treatment of VMS [68-70]. Recently publications have appeared indicating Hormonal agents have been the predominant therapy for that an over-the-counter phytoestrogens-based preparations VMS, but their use decreased substantially following the shifts containing an ERα-selective compound(s) is effective against in risk-benefit ratios that were identified in the Women’s Health VMS but much less than estrogens [45,71]. In our experience, Initiative Estrogen plus Progestin RCT [74]. the effect is more strongly the amelioration of VMS than their cessation. Adverse event information provided in studies of Nonhormonal treatment of postmenopausal symptoms is a J Endocrinol Diabetes Obes 1(2): 1009 (2013) 5/15 Tan et al. (2013) Email: [email protected] Central

subject of great interest today. Although estrogen replacement and fluoxetine compared to placebo in the treatment of VMS. The is the most effective treatment for relief of VMS at present, it initial dose was 10 mg of both fluoxetine and citalopram, and it is contraindicated in about 10% of women with menopausal was increased to 20 mg at 1 month and to 30 mg at the 6-month symptoms [75]. During the past few decades, several new agents visit. Compared to placebo, citalopram and fluoxetine have little on prescription have been used for the management of VMS such effects on VMS [77]. A phase III placebo controlled trial of three as clonidine, selective serotonin reuptake inhibitors (SSRIs), doses of citalopram for the treatment of VMS revealed that serotonin norepinephrine reuptake inhibitors (SNRIs) and VMS scores and frequencies showed significant improvement gabapentin (see Figure 3 and Table 1-3) for randomized controlled citalopram over placebo, with no significant differences among trials comparing the intervention group (nonhormonal) with doses. Reductions in mean VMS scores were 23%, 49%, 50% and ERTSelective or MHT Serotonin for the relief Reuptake of VMS. Inhibitors (SSRIs) 55% for placebo and 10, 20 and 30 mg of citalopram, respectively [80]. Kalay et al. evaluated the efficacy of citalopram on VMS and the combined effect of citalopram and hormone therapy (HT) SSRIs have been investigated for VMS treatment with mixed on VMS in women inadequately responsive to MHT alone [78]. results [76-81]. Commonly used SSRIs are; fluoxetine 20 mg/ One hundred postmenopausal women were equally divided into day, paroxetine 5-12.5 mg/day, citalopram 20 mg/day and four groups: 1) citalopram (10-20 mg), 2) placebo, 3) citalopram escitalopram 10-20 mg/d [80,81]. (10-20 mg) plus MHT (CEE 0.625 mg/d or estradiol 2 mg/d plus MPA 5 mg/d) or 4) placebo plus MHT. After 8 weeks of treatment, A large trial of paroxetine [82] showed a significant reduction mean VMS scores improved significantly in all groups with (approximately 50–60%) in the frequency of VMS when used reduction rates of 37% in group 1, 13% in group 2, 50% in group in the short term. In 2013, FDA approved low-dose mesylate 3 and 14% in group 4 (group 1 vs. group 2: p=0.001; group 3 vs. salt of paroxetine (LDMP) at a dose of 7.5 mg/day for the group 4: p=0.001). In this study, citalopram was found to be an treatment of moderate to severe VMS. Paroxetine mesylate is effective alternative treatment option to MHT [78]. an orally administered psychotropic drug similar to paroxetine hydrochloride [83]. Paroxetine mesylate is FDA-approved for the Escitalopram is another commonly used SSRI and 2011 treatment of major depressive disorder, obsessive-compulsive placebo-controlled RCT, evaluated its efficacy and tolerability disorder, generalized anxiety disorder, and panic disorder at [81]. Otherwise healthy women received 10 or 20 mg/d of doses of 20 to 60 mg/d, depending on the indication [84]. LDMP escitalopram or a matching placebo for 8 weeks. 55% of women was developed specifically for the treatment of moderate to severe in the escitalopram group vs 36% in the placebo group reported a VMS associated with menopause, at a dose of 7.5 mg once dailyst decrease of at least 50% in VMS frequency (p=0.09) at the 8-week which is lower than that indicated dose for psychiatric disorders. follow up. These findings suggested that among healthy women, LDMP’s phase 2 and 3 trial results has been presented at the 61 10 to 20 mg/d of escitalopram provides a nonhormonal, off-label Annual Clinical Meeting of the American College of Obstetricians option that is effective and well tolerated in the treatment of VMS and Gynecologists (ACOG) in May 6, 2013 but the data has not [81]. been published as a manuscript yet. Based on the press release Some of the side effects of SSRIs include cardiovascular side by the manufacturer in 2013, LDMP 7.5 mg once daily is both effects (sinus tachycardia, prolonged QT intervals), increased efficacious and well tolerated for the treatment of moderate to Seratoninrisk of suicidal Norepinephrine behavior, weight loss,reuptake headache, inhibitors agitation [86,87]. severe VMS and it is the only FDA approved nonhormonal agent for the treatment of moderate to severe VMS [85]. In addition to paroxetine, citalopram and fluoxetine are two Seratonin norepinephrine reuptake inhibitors (SNRIs; such other SSRIs and an RCT investigated the efficacy of citalopram as venlafaxine, desvenlafaxine) were studied for the treatment + Nonhormonal options* Complementary therapies of VMS [88]. A randomized, double blind, placebo-controlled trial of desvenlafaxine for the treatment of VMS included SSRIs Phytoestrogens 567 postmenopausal women who were assigned to receive -Isoflavones, soy -Paroxetine 7.5 mg/d** desvenlafaxine 100 mg or 150 mg daily or placebo. After 12 -Fluoxetine 20 mg/d -Red clover extracts -Citalopram 20 mg/d weeks, reductions in the number of VMS in the 100 mg, 150 mg, and placebo group were 60%, 66%, and 47%, respectively [28]. SNRIs -Black cohosh -Venlafaxine -Dong quai A double blind placebo-controlled RCT assessed the efficacy of 37.5-75 mg/d -Kava kava venlafaxine at doses of 37.5 mg/d, 75 mg/d, 150 mg/d or placebo. -Desvenlafaxine -Mind-body interventions After 4 week of treatment, median VMS scores were reduced 100-150 mg/d -Acupuncture, hypnosis, 37%, 61%, 61% and 27% respectively [89]. Some of the adverse biofeedback, Clonidine -Relaxing therapies (yoga, effects of SNRIs include , dry mouth, dizziness and anxiety 0.1-0.4 mg x3/d massage) [90]. -Life style changes Gabapentin A double blind randomized controlled trial compared a single Stellate 900 mg/d Ganglion Block dose intramuscular injection of depomedroxyprogesterone Figure 3 acetate (MPA) 400 mg to oral venlafaxine 37.5 mg for 1 week followed by 75 mg daily (n=109 patients in each arm) [91]. During Nonhormonal options and complementary therapies for the relief of the sixth week after randomization, VMS scores were reduced by VMS. 55% in the venlafaxine arm as compared to 79% reduction on J Endocrinol Diabetes Obes 1(2): 1009 (2013) 6/15 Tan et al. (2013) Email: [email protected] Central

Table 1: Main outcome Results and Author andRandomized year trials Typecomparing of study intervention groupComparison with the ERT/MHT of groups in the treatment of VMS. Follow up Author’s conclusion measure magnitude of effect

VMS frequency

change/day at 12 wks: Mean change in MP group: -3.3 (-3.9 to Oral micronized Placebo-controlled -2.7) vs. placebo -1.4 Daily VMS progesterone is Randomized Trial Micronized progesterone (MP) 300 (-2.1, -0.8) frequency and effective for treatment Hitchcock 2012 mg/day (n = 68; mean age=55.5) 12 weeks intensity score of VMS in healthy Micronized Progesterone vs. Placebo (n = 46; mean age=54.4) VMS severity menopause change women in early Placebo change/day at 12 wks: Mean change in MP group: -0.6 (-0.8, -0.5) vs. Placebo -0.4 (-0.5, -0.2)

2.5 mg tibolone + one Cal+D tablet Both tibolone and (n=43; mean age= 51±3) Tibolone vs control: CEE/MPA are effective Randomized controlled trial 0.625 mg conjugated p<0.001 treatment on VMS in relieving VMS + 2.5 mg Efficacy of CEE/MPA vs. Ziaei S 2010 6 months comparing to control. (Tibolone+Cal+D) vs. CEE/ Medroxyprogesterone (CEE/MPA) control: p<0.001 No difference MPA vs. control (n=41; mean age= 51±2) Tibolone vs. CEE/ comparing tibolone Control group (Cal+D tablet; n=46; MPA: NS with CEE/MPA mean age= 52±4)

68 women were assigned to one of Isoflavone: the two treatment groups. significant decrease isoflavone (n = 33, mean in VMS total score) age=53.9 ± 0.9): 300 mg of the VMS of 1.8 times (p <

standardized soy extract with a 0.01 compared to Double blind single center Both isoflavone and medium dose of 120 mg isoflavones/ baseline). randomized controlled trial vaginal pH, estrogen are effective Kaari C 2006 day as glycoside and aglycone (60 6 months vaginal cytology in relieving VMS after 6 mg twice a day) or Estrogen: significant Isoflavone vs. estrogen changes months of treatment Estrogen (n = 35, mean decrease in VMS age=53.7 ± 0.9): one capsule of 0.625 (total score) of mg conjugated equine estrogens and 2.8 times (p < other capsule with glucose 0.625 mg 0.001 compared to (placebo) baseline).

Group 1: citalopram (10-20 mg, n=25, mean age=53.5±5.3)

Single-blind randomized Group 2: placebo (n=25, mean Mean scores

controlled trial age=51.7±4.6) Group 1: 37% significantly improved Reduction rate in Group 3: citalopram (10-20 mg) plus Group 2: 13% in all groups. It is Kalay AE 2007 VMS compared to 8 weeks Citalopram vs. placebo vs. MHT (CEE 0.625 mg or estradiol Group 3: 50% possible that addition baseline citalopram plus MHT vs. 2mg+MPA 5mg/d; n=25, mean Group 4: 14% of citalopram increases placebo plus MHT age=52.5±4.3) the efficacy of HRT

* Group 4: placebo plus MHT; n=25, mean age=53.6±4.7) P value not reported. Significance determined by 95% confidence interval. No wash out period and drop-out rate not reported • Cal+D: Calcium plus vitamin D NS: Not statistically significant the MPA arm (p<0.001). It was concluded that a single MPA may than placebo (13 vs. 26 days, p = 0.006). The placebo effect was effectively reduce VMS than does venlafaxine [91]. high (57%). Nausea was the most common adverse event with In a 2012 double-blind, randomized, controlled trial desvenlafaxine, was generally mild to moderate, and resolved including 35 sites in Europe, two sites in South , and one within the first 2 weeks [92]. I that study, desvenlafaxine was not site in , Bouchard et al. evaluated the efficacy and safety superior to placebo in relieving mild to moderate VMS during the of desvenlafaxine (100 mg/d) compared to tibolone (2.5 mg/d) study period of 12 weeks [92]. or placebo for menopausal vasomotor symptoms [92]. The In terms of safety concerns, European Agency cited primary endpoint was the reduction in the average daily number an increase in cardiovascular events and hepatotoxicity with of moderate and severe hot flushes at weeks 4 and 12. At week 12, the reduction of the average daily number of moderate and desvenlafaxine compared to placebo in postmenopausal women severe hot flushes for desvenlafaxine was similar to placebo [93,94]. Desvenlafaxine is FDA-approved for treating depression (p=0.92), although time to 50% reduction was significantly less but not VMS in postmenopausal women [94]. J Endocrinol Diabetes Obes 1(2): 1009 (2013) 7/15 Tan et al. (2013) Email: [email protected] Central

Table 2: Results and Randomized trials comparing intervention group with the ERT/MHT in the treatmentMain outcome of VMS. Author and year Type of study Comparison of groups Follow up magnitude of Author’s conclusion measure effect

Reduction in the VMS composite 0.625 mg/d of conjugated score for both estrogens (n = 20, mean Randomized, double-blind estrogen (72%, age=51.5±4.9) or VMS composite score, Gabapentin appears to be trial P = 0.016) and Placebo (n = 20, mean age- which takes into as effective as estrogen Reddy SY 2006 12 weeks gabapentin (71%, postmenopausal VMS 52.2±4.2), or account both severity in the treatment of Conjugated estrogens vs. P = 0.004) was Gabapentin titrated to and frequency of VMS placebo vs. Gabapentin greater than 2,400 mg/d (n = 20, mean the reduction age=51.2±4.4) for 12 weeks. associated with placebo (54%) Percent reduction treatment Gabapentin 600 mg was Prospective single blind Gabapentin 600 mg/night at the end of as effective as low-dose randomized study (n=23, mean age=48.3±2.3) Relief of VMS (percent transdermal estrogen Aguirre W 2010 or transdermal 25 μg/day reduction at the end of 8 weeks compared to in controlling moderate Gabpentin vs. Transdermal estradiol per week (n=22, mean treatment) baseline menopausal women to severe VMS in post- estradiol age=48.7±2.3) Gabapentin: 58.9% Estrogen: 70.1%

Group 1: Black cohosh, 160 mg daily (mean age= 52) Did not differ Group 2:multibotanical with between the herbal

Randomized, double-blind, black cohosh, 200 mg daily interventions and Black cohosh used in

placebo-controlled trial (mean age=52.2) placebo (P > 0.05 isolation, or as part of a Group 3: multibotanical plus Relief of VMS for all comparisons. multibotanical regimen,

Black cohosh vs. dietary soy counseling (mean compared to baseline The difference shows little potential as an Newton KM therapy versus Multibotanical with black age=52.5) in each group and 1 year for hormone important therapy for relief 2006 cohosh vs. Multibotanical Group 4: conjugated difference among of VMS vasomotor plus dietary counseling vs. equine estrogen, 0.625 groups placebo was −4.06 CEE with or without MPA mg daily, with or without Hormone therapy is the

vs. placebo medroxyprogesterone acetate, symptoms per day most effective among all 2.5 mg daily (mean age=52.3) at 12 months (P < or Group 5:placebo (mean 0.001). age=52) Acupuncture (30 min, 2 times weekly for first 2 weeks and Within-group: 1 time weekly for 10 weeks, P < 0.05 during and Prospective single blinded plus electrical stimulation (2 Hz, after treatment in Electroacupuncture may randomized trial 4 points used, n = 23, mean Relief of VMS (Mean both groups. be a possible treatment of Fisk 2008 Hormone therapy (HT; 24 months hormone therapy age=56.5) frequency/day) Intergroup: HT is vasomotor symptoms for Electroacupuncture (EA) vs more effective than women with breast cancer. sequential estrogen/ EA, the P-value was progestagen, n = 18, mean not reported * age=53.4) P value not reported. Significance determined by 95% confidence interval. No wash out period and drop-out rate not reported • Cal+D: Calcium plus vitamin D NS: Not statistically significant

Although some of the placebo controlled randomized trials Concerns have been raised regarding the interference of SSRIs comparing venlafaxine or desvenlafaxine with placebo showed with tamoxifen metabolism. Tamoxifen is mainly metabolized by superior effects of SNRIs, we need prospective randomized trials CYP 3A and CYP 2D6 to the active metabolite endoxifen. comparing the efficacy and safety of SNRIs to the gold standard Studies have shown that paroxetine and fluoxetine are very estrogen to better determine the efficacy of these non-hormonal potent CYP 2D6 inhibitors, and so reduce endoxifen levels, agents in the treatment of VMS. whereas venlafaxine is the least potent inhibitor [95]. Therefore, We were unable to find any double blind randomized at least for tamoxifen users, agents other than paroxetine and controlled trial studies comparing venlafaxine and desvenlafaxine fluoxetineGabapentin may be preferred [96] (See Figure 4 “Warnings”). with the gold standard estrogen for the treatment of VMS. Currently a study entitled “comparative efficacy of low-dose estradiol and venlafaxine XR for treatment of menopausal Gabapentin is commonly used in the management of symptoms” is recruiting participants for the comparison of these neuropathic pain and epilepsy; however, it is not FDA approved two groups (cinicalTrials.gov identifier: NCT01418209). for the treatment of menopausal VMS. A RCT involving women J Endocrinol Diabetes Obes 1(2): 1009 (2013) 8/15 Tan et al. (2013) Email: [email protected] Central

Table 3: Author and Main outcome Results and magnitude Randomized trialsType comparingof study interventionComparison group with of thegroups ERT/MHT in the treatment of VMS.Follow up Author’s conclusion year measure of effect

At weeks 4 and 12, women Multicenter double taking BZA/CE (74% for blind Randomized, BZA 20 mg/CE 0.45 mg placebo-controlled trial BZA 20 mg / CE 0.45 mg (n=122, Change from baseline and 80% for BZA 20/CE BZA 20 mg paired with of 12 week duration mean age:53.5 ) in the average daily 0.625 mg) had significant CE 0.45 mg or 0.625 mg is Pinkerton JV BZA 20 mg / CE 0.625 mg (n=125, At 4 and 12 number and severity reductions from baseline effective with short term 2009 Bazedoxifene (BZA) 20 mean age:53 ) severe VMS weeks postmenopausal women of moderate and in the mean daily number safety for treating VMS in mg/ CE 0.45 mg or and severity of moderate BZA 20 mg / CE 0.625 Placebo (n = 63, mean age: 53.6) to severe VMS compared mg or with placebo at 4 and 12 Placebo weeks follow up Prospective The tibolone group randomized double exhibited better sexual blind hormone therapy 2.5 mg tibolone (n=42, mean function compared with controlled trial of 12 age:51) the E2/NETA and Ca/Vit E2/NETA exhibited a week duration vasomotor symptoms Polisseni AF 50 mg Ca/VitD3 (n=44, mean Quality of life and D3 groups. superior response for 12 weeks 2013 age:53) Improvement of VMS E2/NETA was superior Tibolone or calcium 1 mg E2/NETA (n=44, mean to tibolone and Ca/ compared to tibolone carbonate + vitamin D3 age:53) Vit D3 treatment for (Ca/VitD3) or estradiol vasomotor symptoms improvements in + norethindrone acetate * (E2/NETA) P value not reported. Significance determined by 95% confidence interval. No wash out period and drop-out rate not reported • Cal+D: Calcium plus vitamin D NS: Not statistically significant

•Possible acute liver disease with black cohosh use. to be as effective as estrogen in the treatment of postmenopausal VMS at given doses [98]. •Paroxetine should be avoided in women receiving tamoxifen because it reduces the formation of one of the major tamoxifen active metabolites . In 2010, Aguirra et al compared gabapentin versus low- •SSRIs must be used with caution in women with breast cancer receiving dose transdermal estradiol for treating postmenopausal adjuvant tamoxifen therapy since SSRIs reduce the metabolism of tamoxifen to women with moderate to very severe VMS [99]. A total of 45 its most active metabolite, endoxifen. postmenopausal women with moderate to very severe VMS were •MHT increases the risk of invasive breast cancer, which may occur within 3 to prospectively randomized to receive oral gabapentin (600 mg/d) 5 yr of initiation and rises progressively beyond that time or transdermal 25 µg/day estradiol per week. VMS intensity and •Gabapentin may increase the risk of suicidal thoughts or behavior frequency were assessed at baseline and at 1, 4 and 8 weeks. VMS •Desvenlafaxine may be associated with increase in cardiovascular events and intensity and frequency significantly decreased for both groups hepatotoxicity at 1, 4 and 8 weeks of treatment as compared to baseline. This decrease was statistically more evident for the transdermal Figure 4 estradiol group. Although the percentage of VMS intensity and Warnings. frequency reduction at the end of the treatment was higher for estradiol, this was not statistically significant and both treatment options were effective in alleviating VMS (transdermal estradiol without a history of breast cancer examined the efficacy of vs. gabapentin; 68.2% vs. 60.6% for intensity and 70.1% vs. gabapentin for the treatment of VMS [97]. Gabapentin at 900 mg 58.9% for frequency respectively) [99]. per day was associated with a 45% reduction in VMS frequency Gabapentin could be considered effective in the treatment and a 54% reduction in VMS composite score (frequency and of VMS and should be considered as a possible alternative severity combined into one score) from baseline compared with when estrogen therapy is not desired however there are some 29% for placebo [97]. Reddy et al. performed a randomized, concerns about its safety. Some of the side effects of gabapentin double blind, placebo-controlled trial to assess the efficacy of estrogen and gabapentin in the treatment of moderate-to-severe are dizziness, drowsiness and peripheral [100]. In 2008, VMS [98]. Participants were randomly assigned to receive either the FDA issued a Public Health Advisory regarding the potential 0.625 mg/day of CEE (n = 20), placebo (n = 20), or gabapentin for any anticonvulsant, including gabapentin, to increase the risk titrated to 2,400 mg/day (n = 20) for 12 weeks. The reduction of suicidal thoughts or behavior [94,101]. Therefore prospective in the VMS composite score for both estrogen (72%, P = .016) clinical trials may be required to investigate not only the efficacy and gabapentin (71%, P = .004) was greater than the reduction but also the safety of gabapentin in the treatment of VMS in associated with placebo (54%) at the conclusion of the 12th Clonidinepostmenopausal women. week. The extent of reduction in VMS composite score, however, was not significantly different between estrogen and gabapentin (P = 0.63). Although this was a small study, gabapentin appeared Clonidine is a α-adrenergic agonist agent. It may relieve VMS J Endocrinol Diabetes Obes 1(2): 1009 (2013) 9/15 Tan et al. (2013) Email: [email protected] Central

by reducing peripheral vascular reactivity [102]. It is usually up duration of 1 year [110]. CEE was associated with significant given transdermally, starting with a patch that delivers 0.1 mg/ relief of VMS compared to any of the other groups. There was day, which is left in place for one week. Clonidine also may be no difference between placebo and any of the herbal treatments given orally in doses of 0.1 to 0.4 mg three times daily. over all of the follow-up points. Some cautions have been raised about possible adverse effects, such as acute liver disease and In a randomized, double blind, placebo-controlled clinical gastrointestinal side effects with black cohosh use (see Figure 4 trial, Pandya et al. evaluated the effectiveness of oral clonidine “Warnings” box) [103,107]. (0.1 mg/d) compared to placebo for 8 weeks for control of VMS associated with tamoxifen therapy in postmenopausal women Dong quai root, Evening primrose oil, Kava kava, Ginseng root with breast cancer. The mean decrease in VMS frequency was have not been shown to have any benefit for VMS relief [111]. greater in the clonidine group than in the placebo group after The FDA has issued a warning to patients and providers about 4 weeks of treatment (37% compared with 20%). However the potentialOTHER harm COMPLEMENTARY with kava kava [103]. THERAPIES available evidence for its efficacy is contradictory. According Lifestyle changes, mind-body interventions to a meta-analysis including 10 randomized controlled trials, the severity of VMS was not improved in 6 of the 10 trials with clonidine [103]. Adverse events included dry mouth, insomnia and drowsiness, and occurred more commonly with clonidine, Currently, there are limited data from observational particularly at higher doses [103]. A 2011 double blind placebo- studies that lifestyle modifications such as loose clothing, controlled RCT compared the average daily VMS scores among sipping cold drinks, avoiding spicy food, and keeping a lower patients treated with venlafaxine 75 mg, clonidine 0.1 mg, room temperature can improve mild vasomotor symptoms or placebo daily for 12 weeks [104]. The reduction in VMS [112,113]. A recent review of the literature on the efficacy of severity scores was similar between venlafaxine and clonidine relaxation techniques such as yoga on VMS control concluded group (41%) at 12 weeks of treatment and the reduction was that most trials had positive results. However, the trials were significantly higher compared to the placebo group (29%) heterogeneous, designed with small sample sizes and included a [104]. To the best of our knowledge, there are no double blind variety of interventions and outcome measures. Therefore, more controlled trials comparing clonidine with ERT or MHT regarding large well-designed randomized estrogen-controlled trials are its efficacy in the treatment of VMS. needed to further evaluate the efficacy of these various forms of relaxationMind-body techniques therapies; on VMS hypnosis, relief [62,114]. acupuncture Some of the common side effects of clonidine include difficulty sleeping, mouth dryness, constipation, itchiness (if used as a patch)COMPLEMENTARY and drowsiness [105]. AND ALTERNATIVE NON- VMS are often associated with anxiety and stress. Therefore, it HORMONAL THERAPIES has been proposed that hypnosis may act to reduce the frequency Botanicals and intensity of VMS [62]. In a prospective study including sixty female breast cancer survivors, significant improvements in self-reported anxiety, depression, interference of VMS on daily activities, and sleep were observed for patients who received The findings of WHI study have contributed to the public’s the hypnosis intervention compared to the no treatment group growing interest in complementary and alternative approaches [115]. Further estrogen-controlled studies are needed to confirm for the management of vasomotor symptoms. In general, research these findings. on these approaches is scant and research to date has focused primarily on botanicals, with a few studies of other approaches Acupuncture involves the use of thin needles inserted into [103,106].Black cohosh (Actacea racemosa or Cimicifuga specific points of the body. When electro-acupuncture (EA) was racemosa) compared with hormone replacement therapy, hormone therapy was more effective than EA [116]. The evidence is not convincing to suggest acupuncture as an effective treatment for VMS in In the English-language literature, there is little evidence that patientsExercise with breast cancer [116]. black cohosh is an effective treatment for VMS [107,108]. A 2009 randomized, double blind clinical trial compared black cohosh, red clover and placebo for the relief of VMS. 89 women were There was no evidence from randomized controlled trials randomized to receive black cohosh 128 mg/day, red clover 120 whether exercise is an effective treatment relative to other mg/day, hormone therapy (625 μg estrogen and 2.5 mg MPA) interventions or no intervention in reducing VMS in symptomatic or placebo. At the end of 12 months the reduction in VMS was women [117]. There are no randomized estrogen-controlled 34% in the black cohosh group, 57% in the red clover group, 63% trialsStellate examining ganglion the efficacyblock (SGB)of exercise in managing VMS. in the placebo group, and 94% in the hormone therapy group. Thus, neither red clover nor black cohosh significantly reduced VMS [109]. In a double blind placebo-controlled trial, Newton et The stellate ganglion is present in only 80% of the population. al. tested the efficacy of 4 regimens (1- black cohosh 160 mg/d, In a recent study, 13 survivors of breast cancer (in remission) 2- mutibotanical with dietary soy, 3- multibotanical with black with severe VMS were treated with SGB at the anterolateral cohosh 200 mg/d, 4- CEE 0.625 mg/d with or without MPA 2.5 aspect of the C6 vertebra. Patients recorded VMS in a daily diary mg/d) compared to placebo for the relief of VMS with the follow by use of the Hot-Flash Score. The total number of VMS decreased J Endocrinol Diabetes Obes 1(2): 1009 (2013) 10/15 Tan et al. (2013) Email: [email protected] Central

from a mean of 79.4 per week before the procedure to a mean The severity of VMS were reduced by 83% for of 49.9 per week during the first 2 weeks after the procedure. standard-dose estrogen (0.635 mg CEE) and by 63% This study suggested that SGB might provide survivors of breast for low-dose estrogen (0.3, 0.45 mg CEE). cancer with relief from VMS and sleep dysfunction with few or no side effects [118]. We did not find any randomized clinical trials comparing“Bioidentical” SGB with hormone ERT/MHT therapy for the treatment of VMS. SSRIs and SNRIs, Gabapentin and Clonidine showed a mild to moderate effect on reducing VMS in women with a history of breast cancer. Bioidentical hormone therapy (BHT) is a confusing marketing term. It is most often used to describe custom-made hormone Phytoestrogens (isoflavones, soy), black cohosh, therapy formulations (called BHT) that are compounded for an dong quai, evening primrose oil, ginseng extract, individual according to a healthcare provider’s prescription [119]. kava kava, vitamin E, red clover leaf, hypnosis, Custom compounding of hormone therapy may provide different acupuncture are either ineffective or not clinically significantly efficacious in the treatment of VMS doses ingredients (eg, ), and routes of administration (eg, subdermal implants) that are not government approved. FDA has VMS: vasomotor symptoms ruled that compounding pharmacies have made claims about the Figure 5 safety and effectiveness of BHT unsupported by clinical trial data Key Evidence. and considered to be false and misleading [119]. BHT is not an evidence-based therapy and therefore is not included in detail in thisCONCLUSION review. NAMS suggested limited evidence with relaxing therapies such as yoga, massage, mediation, leisure baths, and slow breathing techniques, mind-body therapies such as hypnosis, acupuncture ERT/MHT is the most effective treatment for moderate and exercise [8]. A new approach to hormone therapy is to severe VMS and is a reasonable choice in the absence of combining a SERM with one or more estrogens or TSECs. An contraindications. If the patient has not had a hysterectomy, optimal TSEC will reduce VMS, increase bone mass density, and estrogen with an added progestogen is recommended. The have favorable effects on vaginal cytology and symptoms without patient should be informed about the potential side effects and unfavorable effects on breast and endometrium [44]. Future risks associated with hormone therapy. 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Cite this article Tan O, Pinto A, Carr BR (2013) Hormonal and Non-Hormonal Management of Vasomotor Symptoms: A Narrated Review. J Endocrinol Diabetes Obes 1(2): 1009.

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