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Hormonal and Non-Hormonal Management of Vasomotor Symptoms: a Narrated Review

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Hormonal and Non-Hormonal Management of Vasomotor Symptoms: a Narrated Review 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 Infertility, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Dallas, TX 75390 and ReproMed Fertility 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 estrogens and estrogen-progestogen combinations. However, both physicians and patients became concerned about hormone-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 estrogen receptor (ER) ligands is unequivocally the most effective treatment for VMS. In most studies, the selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tibolone, clonidine 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 cancer receiving adjuvant tamoxifen therapy since SSRIs reduce the metabolism of tamoxifen to its most active metabolite, endoxifen. 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 progesterone is effective for treatment of VMS in early postmenopausal women. Bazedoxifene/conjugated estrogen may be a promising alternative to hormone therapy for the treatment of VMS. The effects of phytoestrogens 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 side effect 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, alcohol consumption, carcinoid syndrome, abruptness of the loss of estrogen activity [2,3]. dumping syndrome, and medications such as nitrates, niacin, It was for decades the approach to offer FDA- (Food and Drug gonadotropin-releasing hormone agonists, 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 luteinizing hormone 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 Estradiol: 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- • Vaginal estrogen (Estradiol acetate; *Femring estradiol, 0.014 mg/day Randomized controlled prospective, single- or double-blinded vaginal ring): 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 Progestogens Estrogen-Progestogen Combinations Oral continuousa: (CE) and (MPA), Estrogen plus Progestogen replacement therapy (MHT): • Medroxyprogesterone acetate (MPA): 2,5-5-10 mg/d • 0.625 CE and 2.5 or 5 mg MPA • Megestrol 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 norethisterone 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 Levonorgestrel 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 conjugated estrogens 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
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