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ENERAL GYNECOLOGY

asomotor symptoms in menopause: physiologic conditionnd central nervous system approaches to treatment

ndrea J. Rapkin, MD

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ife expectancy for women is increas-ing worldwide. The mean lifespan

or women in the United States is ap-roximately 80 years,1 and women whore currently 75 years old have 12.4 ad-itional years of life expectancy.2 There-

ore, most women can expect to spend aignificant portion of their lives in a post-

enopausal state. It is estimated that ap-roximately 30 million women in thenited States are now in or past meno-ause and that an additional 6 millionomen will reach this stage during thisecade.3,4

The decline in estrogen levels that isssociated with menopause results in aide range of symptoms. The most com-on are vasomotor symptoms, which

nclude hot flashes (also referred to asot flushes) and night sweats. Meno-ausal symptoms may also include diz-iness, rapid irregular heartbeat, atro-hic vaginitis, bladder irritability, moodhanges, sleep disturbances, headaches,yalgias, arthralgias, difficulty concen-

rating, memory impairment, and gen-ral malaise.5-7 The North American

enopause Society position statementodified the language that is used to de-cribe vasomotor symptoms of meno-ause. They define vasomotor symp-oms as a global term that encompassesot flashes and night sweats.8 This posi-ion statement does not review treat-

rom the Department of Obstetrics andynecology, David Geffen School ofedicine at UCLA, Los Angeles, CA.

eceived Nov. 29, 2005; revised April 12,006; accepted May 4, 2006.

eprint requests: Andrea J. Rapkin, MD,epartment of Obstetrics and Gynecology,avid Geffen School of Medicine at UCLA,0833 LeConte Ave, Los Angeles, CA 90095-740; [email protected].

002-9378/$32.002007 Mosby, Inc. All rights reserved.

moi: 10.1016/j.ajog.2006.05.056

ent of mood changes or sleep distur-ances along with vasomotor symptoms.owever, considering sleep distur-

ances in the context of hot flashes andight sweats is logical because a numberf studies have demonstrated strong re-

ationships between self-reported hotashes and sleep complaints.9 In addi-

ion, treatments that reduce the fre-uency of hot flashes can also improveood,10,11 which supports the view that

hese disturbances should be taken intoccount with the treatment of vasomotorymptoms.

Menopausal vasomotor symptomsccur in as many as 74% of menopausalomen,12 and evidence indicates that

hese symptoms are present in higherercentages (up to 88%) of perimeno-ausal women.13-15 These symptomsenerally subside within 1 year; however,or some women, the symptoms mayersist for more than 30 years.16 Further-

OBJECTIVE: The decline in concentrations orise to a range of physiologic and psycholoand quality of life significantly. Most notabflashes and night sweats) and mood and

STUDY DESIGN: This article reviews the pvasomotor symptoms and centrally active, nefficacy for their treatment.

RESULTS: Despite the emergence of a ransymptoms, a need still exists for safe and ethe underlying thermoregulatory mechanisto avoid hormone therapy or for whom ho

CONCLUSION: The availability of centrallysymptoms with risks and benefits clearly dtrials has the potential to allay safety concthese common symptoms.

Key words: menopause, selective serotonnorepinephrine reuptake inhibitor, vasomo

Cite this article as: Rapkin AJ. Vasomotor symptonervous system approaches to treatment. Am J

ore, they can have a marked negative r

FEBRUARY 2007 Am

mpact on health-related and globaluality of life (QOL)17-19 and oftenrompt visits to health care profession-ls.15

Despite high prevalence and deleteri-us effects of symptoms on QOL, manyomen with menopausal symptoms doot seek treatment or receive therapy for

hese symptoms.20 Results from 2 largeurveys that were conducted across Eu-ope indicated that most women sur-eyed believed that they needed more in-ormation about hormone replacementherapy,21,22 which underscores the needor physicians to educate women aboutew and effective therapies for meno-ausal symptoms and to treat them withedications that meet their individual

eeds.Hormone therapy (HT) has been the

ornerstone of the management ofenopausal symptoms for many years

nd has been demonstrated repeatedly to

onadal hormones during menopause giveschanges that may impact a woman’s healthmong these are vasomotor symptoms (hotp disturbances.

iologic condition underlying menopausalormonal therapies that have demonstrated

of nonhormonal treatments for vasomotortive therapeutic options that directly targetfor women who want treatment but preferne therapy is contraindicated.

tive therapies for menopausal vasomotored by results from well-designed clinical

s that are associated with the treatment of

euptake inhibitor, serotonin-symptoms

in menopause: physiologic condition and centraltet Gynecol 2007;196:97-106.

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erican Journal of Obstetrics & Gynecology 97

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Reviews General Gynecology www.AJOG.org

9

OL.23-25 However, the treatment land-cape for menopausal symptoms hashanged dramatically since the publica-ion of the Women’s Health Initiativend the Heart and Estrogen/Progestineplacement Study and follow-up.26-28

t has become clear that initial interpre-ations of Women’s Health Initiative andeart and Estrogen/Progestin Replace-ent Study substantially overestimated

he risks of HT for the treatment ofenopausal symptoms. Both trials were

esigned to examine long-term effects ofT for the reduction of coronary heart

isease in an older postmenopausal pop-lation. Their conclusions therefore areot generalizable to short-term treat-ent of a younger, perimenopausal pop-

lation.29-31 Still, the results from theserials have increased dramatically the in-erest of health care practitioners and pa-ients in nonhormonal therapies for

enopausal symptoms. This articleombines a discussion of the physiologicondition that underlies vasomotorymptoms, which includes the interplayetween estrogen, serotonin, and nor-pinephrine, with a review of the cur-ently published clinical trials of neuro-ctive therapies, including not only theelective serotonin reuptake inhibitorsSSRIs) and serotonin-norepinephrineeuptake inhibitors (SNRIs), but also the-adrenoceptor antagonists and antido-aminergic agents that have been stud-

ed for the treatment of menopausalymptoms.

Other compounds, which include ti-olone, selective estrogen receptor mod-lators, and phytoestrogens (found inoybeans, black cohosh, whole grains, le-umes, and flaxseed), and other alterna-ive nonprescription compounds arelso available for the treatment of meno-ausal symptoms. However, a full dis-ussion of these treatment options haseen published previously and is beyondhe scope of this review.32-34

ITERATURE SEARCH METHODSPubMed search that was limited to

linical trials that were published in En-lish was conducted with the searcherms hot flash or hot flush or vasomotor
ymptoms (all fields). We eliminated all n
8 American Journal of Obstetrics & Gynecology

eferences in which vasomotor symp-oms were addressed as side effects ratherhan outcome; in which the test articleas a hormone or a hormone modula-

or, a herbal supplement, soy/isoflavone,r other phytoestrogen; and in whichonmedicinal interventions (eg, mag-ets, behavioral therapy) were used, be-ause they were considered outside thecope of this review. The remaining arti-les are summarized in the Table.

HYSIOLOGIC CONDITION OF

ENOPAUSAL VASOMOTOR

YMPTOMS

he occurrence of vasomotor symptomsn most women is correlated closely withstrogen withdrawal that occurs withatural or surgical menopause. The keyole of estrogen in menopausal symp-oms is supported by the fact that hor-

one replacement is generally acknowl-dged as the most effective therapy foreducing their occurrence.23-25 How-ver, estrogen withdrawal alone does notxplain the cause of menopausal vasomo-or symptoms. This is evidenced by the ob-ervation that there is no significant corre-ation between plasma hormone levels andhe occurrence of vasomotor symptoms.35

strogen withdrawal therefore is necessaryut not sufficient to explain the occurrencef menopausal symptoms.36

A growing body of evidence supportshe hypothesis that hot flashes resultrom the physiologic response to a

arked narrowing of the hypothalamichermoregulatory set point or neutralone (Figure 1).36 This change in setoint increases the chances of sensationf intense heat in response to internalnd environmental triggers and subse-uent activation of heat loss responses,hich include cutaneous vasodilation

nd sweating.16,36 It is assumed that theenopause-associated reduction in cir-

ulating levels of gonadal hormonesives rise to this change in hypothalamicunction. However, the relationship be-ween these events is complex, and thexact trigger that induces a change inhermoregulatory set point activity inhe hypothalamus during menopause is
ot understood fully.7 a
FEBRUARY 2007

HERMOREGULATORY SETOINThe key role of a change in the hypotha-

amic thermoregulatory set point or neu-ral zone in the hot flush cascade is un-erscored by the fact that these events arereceded by an increase in core bodyemperature that does not result fromeripheral vasoconstriction or elevatedetabolic rate.37,38 Perspiration and va-

odilation are classic mechanisms of heatoss that are activated during hot flashes.hese responses contribute to night

weats and are initiated by activity in theedial preoptic area of the hypothala-us.24 The changes in hypothalamic

unction that are thought to underlie hotashes and associated symptoms appear

o be related closely to changes in the lev-ls of biogenic amine neurotransmittershat occur in menopausal women.

EUROTRANSMITTER CHANGESN MENOPAUSEstrogen has complex effects in the cen-

ral nervous system (CNS). Menopause-ssociated reductions in circulating es-rogen could lead to imbalances ineurotransmitter levels in the hypothal-mus and other portions of the CNS andltimately result in hot flushes in suscep-

ible individuals. It has been suggestedhat estrogens may alter the activity ofoth the noradrenergic and serotonergicystems by modulating the levels of theseeurotransmitters in the brain. Bothorepinephrine and serotonin are

hought to be involved in the regulationf temperature homeostasis in the hypo-halamus. During menopause, dimin-shed levels of gonadal hormones mayead to instability in CNS concentrationsf both norepinephrine and serotonin,hich results in alterations in thermoreg-lation (eg, a reduced neutral zone) and an

ncreased occurrence of hot flashes.7,39

orepinephrinelarge body of evidence indicates that

orepinephrine plays a central role in theathophysiologic condition of hotashes (Figure 2).36 The involvement oforepinephrine in central thermoregu-

ation and the etiology of hot flashes isupported by results from experimental
nimal studies that showed that in-

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www.AJOG.org General Gynecology Reviews

reased CNS levels of norepinephrine areorrelated with a narrowing of the ther-oneutral zone.36,40 Freedman38 re-

orted that plasma levels of 3-methoxy--hydroxyphenylglycol, a metabolite ofrain norepinephrine and an indicator

TABLEEffects of centrally active drugs* o

Drug Population† Design

Citalopram (SSRI) Postmenopausal, some withhistory of breast cancer(n � 18)

Prospective

...................................................................................................................Women with inadequate

benefit from venlafaxine(n � 22)

Prospective

...................................................................................................................Postmenopausal (n � 150) Placebo-con

blind...................................................................................................................Fluoxetine (SSRI) Postmenopausal (n � 150) Placebo-con

blind...................................................................................................................

Postmenopausal, some withhistory of breast cancer(n � 68)

Double-blincross-ove

...................................................................................................................Sertraline (SSRI) Postmenopausal (n � 15) Uncontrolled

open tria...................................................................................................................Fluvoxamine (SSRI) Women with oophorectomy

(n � 42)Open trial,

estrogen...................................................................................................................Paroxetine (SSRI) Men who received androgen

ablation (n � 22)Prospective

...................................................................................................................Women with history of

breast cancer (n � 27)Pilot trial


blind, ran...................................................................................................................

Women with hot flashes (n� 107)

Placebo-conblind, rancross-ove

...................................................................................................................Women with breast cancer

(n � 13)Uncontrolled

...................................................................................................................Venlafaxine (SNRI) Women with history of

breast cancer, men whounderwent androgenablation (n � 28)

Pilot

...................................................................................................................Women with history of

breast cancer (n � 191)Double-blin

...................................................................................................................Postmenopausal (n � 102) Open-label

phase of2000

...................................................................................................................Breast cancer (n � 30) Open-label

...................................................................................................................Men who underwent

androgen ablation (n �21)

Uncontrolled


blind, ran

...................................................................................................................Gabapentin Breast cancer (n � 371) Placebo-con

blind, ran...................................................................................................................

Breast cancer (n � 22) Uncontrolled


blind, ran

...................................................................................................................Postmenopausal, some with

history of breast cancer(n � 20)

Prospectivepilot

f central noradrenergic activity, in- o

reased significantly after a hot flash in 9enopausal women. This suggests that

lterations in CNS levels of this neuro-ransmitter changed before the onset ofhis menopausal symptom. This conclu-ion is consistent with results from an-

vasomotor symptoms

DoseDuration oftrial Effect

trial Stepwise, 10 mg, 20 mg 5 wk Reducedcompa

.........................................................................................................................trial Stepwise, 10 mg, 20 mg 4 wk Reduced

.........................................................................................................................d, double- Stepwise, 10 mg, 20

mg, 30 mg9 mo No effect

.........................................................................................................................d, double- Stepwise, 10 mg, 20

mg, 30 mg9 mo No effect

.........................................................................................................................domized, 20 mg/d 4 wk Reduced

.........................................................................................................................ospective 25-50 mg/d Not reported Subjectiv

statisti.........................................................................................................................ared with 50 mg/d, with estrogen 8 wk Reduced

.........................................................................................................................trial 12.5 mg/d, increased to

37.5 mg/d4 wk Reduced

freque.........................................................................................................................

10 mg/d, then 20 mg/d 5 wk Reducedfreque

.........................................................................................................................d, double-zed

12.5 mg/d or 25 mg/d 6 wk Reduced

.........................................................................................................................d, double-zed,atified

10 mg/d, 20 mg/d 9 wk Reduced

.........................................................................................................................n trial 20 mg/d Approximately

4 wkReduced

sleepbaselin

.........................................................................................................................25 mg/d 4 wk Reduced

.........................................................................................................................domized 37.5 mg/d, 75 mg/d,

150 mg/d4 wk Reduced

.........................................................................................................................uation

inzi et al,37.5-150 mg/d 8 wk Reduced

(75 mg

.........................................................................................................................37.5 mg/d 8 wk Reduced

from b.........................................................................................................................n trial 12.5 mg twice daily 5 wk Reduced

baselin

.........................................................................................................................d, double-zed

37.5 mg/d, then 75mg/d

12 wk Improvedassessseverit

.........................................................................................................................d, double-zed

300 mg/d, 900 mg/d 8 wk Reducedat 900

.........................................................................................................................n trial 300 mg, 3 times daily 8 wk Reduced

frequebaselin

.........................................................................................................................d, double-zed

900 mg/d, open-labeldose escalation to2700 mg/d after 12wk

12 wk Reducedmg

.........................................................................................................................le-arm Stepwise, 300 to 600 to

900 mg/d5 wk Reduced

compa

ther study that showed that yohimbine, b

FEBRUARY 2007 Am

n �2-adrenergic antagonist, elevates-methoxy-4-hydroxyphenylglycollasma levels and brain norepinephrinend ultimately triggers hot flashes.41 Theole of norepinephrine in hot flashes alsos supported by clinical results that have

Side effects‡ Study

ity, frequencyith baseline

Mild nausea, dry mouth Barton et al10

..................................................................................................................ity, frequency Loprinzi et al 52

..................................................................................................................Insomnia Suvanto-Luukkonen

et al59

..................................................................................................................Suvanto-Luukkonen

et al59

..................................................................................................................ity, frequency Loprinzi et al 53

..................................................................................................................elioration, no Plouffe et al94

..................................................................................................................ency Nagata et al 58

..................................................................................................................ity,ncreased QOL

Loprinzi et al54

..................................................................................................................ity,ncreased QOL

Somnolence, anxiety Stearns et al49

..................................................................................................................ity, frequency Stearns et al 55

..................................................................................................................ity, frequency Drowsiness, nausea Stearns et al 56

..................................................................................................................ity, improvedared with

Weitzner et al57

..................................................................................................................ency Loprinzi et al 63

..................................................................................................................ity, frequency Appetite loss,

constipation, drymouth

Loprinzi et al64

..................................................................................................................ity, frequency Mild appetite loss, dry

mouth, dissipatingnausea

Barton et al65

..................................................................................................................ity, frequencye

Nausea, dry mouth Biglia et al66

..................................................................................................................ency from Quella et al68

..................................................................................................................ective, no effect on

Dry mouth,sleeplessness,decreased appetite

Evans et al67

..................................................................................................................ity, frequency Loss of appetite Pandya et al71

..................................................................................................................ion, severity,ompared with

Pandya et al95

..................................................................................................................ity at �900 Peripheral edema,

somnolence,dizziness

Guttuso et al70

..................................................................................................................ity, frequencyith baseline

Loprinzi et al96

Continued on page 100.

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drenergic agonist that reduces centraloradrenergic activity.5,42 This agent haseen used with modest efficacy as a treat-ent for women with menopausal vaso-

TABLEEffects of centrally active drugs* oContinued from page 99.

Drug Population† Design

Clonidine (alphaadrenergicagonist)

Postmenopausal (n � 86) Placebo-conblind, cro


blind...................................................................................................................

Women with hot flashes (n� 37)

Placebo-conblind, cro


response


blind, cro...................................................................................................................

Postmenopausal, tamoxifen-induced (n � 194)

Randomizedplacebo-

...................................................................................................................Postmenopausal, tamoxifen-

induced (n � 110)Placebo-con

blind, cro


blind, cro...................................................................................................................Methyldopa (alpha

adrenergicagonist)

Postmenopausal (n � 28) Placebo-conblind, cro


blind, cro

...................................................................................................................Veralipride

(antidopaminergic)Postmenopausal (n � 29)

...................................................................................................................Premenopausal,

gonadotropin-releasinghormoneagonist-inducedhot flashes (n � 36)

Randomizedplacebo-

...................................................................................................................Postmenopausal (n � 40) Randomized

placebo-...................................................................................................................

Postmenopausal (n � 47) Randomizedplacebo-crossove

...................................................................................................................Gonadotropin-releasing

hormone agonist-inducedhot flashes (n � 25)

Open obser

...................................................................................................................Postmenopausal (n � 40) Double-blin

...................................................................................................................Veralipride,

bromocriptine,Liposom,domperdome

Postmenopausal (n � 75) Randomizedplacebo-

...................................................................................................................Mirtazapine Women with history of

breast cancer (n � 22)Prospective

pilot...................................................................................................................Moclobemide

(monoamineoxidaseinhibitor)

Postmenopausal (n � 28) Randomizedplacebo-

...................................................................................................................Propranolol (beta

blocker)Perimenopausal (n � 25) Prospective

randomiz...................................................................................................................

* The entries are the results of a PubMed literature search onif (1) vasomotor symptoms were side effects rather than anphytoestrogen; or (3) trials used nonmedicinal interventions.† Subjects with available data.‡ Where reported to be significant.

otor symptoms.6 w


erotoninerotonin also appears to play a pivotalole in the hot flash cascade (Figure 3).7

strogen withdrawal may be correlated

vasomotor symptoms

DoseDuration oftrial Effect

d, double-er

25-75 �g twice daily 8 wk Reducedfreque

.........................................................................................................................d, double- 0.1 mg/d, transdermally 10 wk Reduced

.........................................................................................................................d, double-er

0.050- 0.075 mg/d 12 wk No effect

.........................................................................................................................d, dose- 0.1, 0.2, 0.4 mg/d 6 wk Reduced

compa

.........................................................................................................................d, double-er

0.1 mg/d 10 wk No effect

.........................................................................................................................ble-blind,lled

0.1 mg/d 8 wk Reducedincrea

.........................................................................................................................d, double-er

0.1 mg/d 8 wk Small bureducefreque

.........................................................................................................................d, double-er

0.050 mg twice daily 13 wk No effect

.........................................................................................................................d, double-er

250-500 mg twice daily 60 d, 14 dwashout

Reduced

.........................................................................................................................d, double-er

375-1125 mg/d 8-16 wk No effectcompasubjecin “troflushes

.........................................................................................................................100 mg/d with raloxifene

60 mg/d6 mo Reduced

.........................................................................................................................ble-blind,lled

100 mg/d 2 mo Reduced

.........................................................................................................................ble-blind,lled

100 mg/d 30 d Reduced

.........................................................................................................................ble-blind,lled,

100 mg/d 80 d Reduced

.........................................................................................................................al trial 100 mg/d 28 d Reduced

severitreporte

.........................................................................................................................domized 100 mg/d compared

with 1.25 mg/destrogen

20 d Reducedseveritestrog

.........................................................................................................................ble-blind,lled

100 mg/d veralipride,3.75 mg/dbromocriptine, 40mg/d im Liposom, 10mg/d domperdome

20 d Reducedseveritcompa

.........................................................................................................................le-arm, 7.5 mg/d, then 15 mg/d,

then 30 mg/d5 wk Reduced

freque.........................................................................................................................ble-blind,lled

150 mg/d or 300 mg/d 5 wk Reduced

.........................................................................................................................ble-blind, 40 mg, 3 times daily 8 wk No effect

.........................................................................................................................

terms hot flash, hot flush, and vasomotor symptoms, limited to come measure; (2) test article was a hormone or a direct hormo

ith a decline in circulating serotonin n

FEBRUARY 2007

evels that could increase the sensitivityf hypothalamic serotonin (5-HT2A) re-eptors. This change may also contributeo a narrowing of the thermoregulatory

Side effects‡ Study

ity,uration

Dry mouth Clayden et al73

..................................................................................................................ency Nagamani et al 74

..................................................................................................................No different from

placeboSalmi and

Punnonen75

..................................................................................................................encyith baseline

Severe fatigue, nausea,headaches,irritability, dizziness

Laufer et al78

..................................................................................................................equency Wren and Brown 76

..................................................................................................................ency,OL

Difficulty sleeping Pandya et al79

..................................................................................................................ificanterity,

Dry mouth,constipation,drowsiness

Goldberg et al77

..................................................................................................................Lindsay and Hart 97

..................................................................................................................ency Nesheim and

Saetre81

..................................................................................................................equencyith placebo,provement

caused by hot

Andersen et al82

..................................................................................................................ashes Morgante et al83

..................................................................................................................ency, severity Hyperprolactinemia Vercellini et al 84

..................................................................................................................ency, severity Melis et al 85

..................................................................................................................ency, severity Increased estradiol,

hyperprolactinemia,galactorrhea

David et al86

..................................................................................................................ency,statistics

Vercellini et al87

..................................................................................................................ency,different than

Wesel et al88

..................................................................................................................ency,drugsith placebo

Mastodynia,galactorrhea

Zichella et al89

..................................................................................................................ity,o statistics

Increase in appetite,dry mouth

Perez et al90

..................................................................................................................ity Tarim et al 91

..................................................................................................................Coope et al92

..................................................................................................................

l trials published in English. References were eliminatedodulator, a herbal supplement, soy/isoflavone, or other

n

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ash occurrences.43,44 After an internalr external thermostimulus, rising con-entrations of ligand stimulate the sero-onin (5-HT2A) receptor, which resultsn a change in the thermoregulatory setoint and a subsequent hot flash sensa-ion. The importance of serotonin in theot flash cascade is underscored by re-ults from a comparison of serotoninevels in women with mild vs moderate-o-severe menopausal symptoms that in-icates an association between concen-ration of serotonin and severity of

enopausal symptoms.45

ood and sleep disturbancesood and sleep disturbances are in-

luded in the array of menopausal symp-oms, and their occurrence may resultrom changes in CNS transmitters,hich include serotonin, norepineph-

ine, dopamine, and endorphins.46 Theentral importance of the relationshipetween estrogens and the serotonin sys-em in mood regulation in women with

enopause is supported by results fromsmall-scale study that demonstrates

hat the blockade of serotonin receptorsith metergoline reversed the positive

ffects of estrogen replacement on moodn perimenopausal women.47 Serotoninlso plays a key role in the regulationf sleep,48 and menopause-associatedhanges in serotonin levels may contrib-te to sleep disorders. This view is sup-orted by the fact that treatment with

FIGURE 1Small core body temperature(Tc) elevations that act withina reduced thermoneutral zonetrigger hot flashes insymptomatic postmenopausalwomen.

reedman RR. Pathophysiology and treatment ofenopausal hot flashes. Semin Reprod Med

005, 23:117-25. Reprinted with permission ofhieme.

n SSRI improves sleep in menopausal

omen.49 Although it has been suggestedhat disturbed sleep in menopause may beue to hot flashes,50 recent results indicatehat this is not entirely the case.51

EUROACTIVE AGENTS FORENOPAUSAL VASOMOTOR

YMPTOMSwide range of neuroactive agents has

een evaluated for the treatment ofenopausal symptoms. Most of theseedications have been tested in rela-

ively short-term, small-scale clinical tri-ls. However, these drugs have been usedxtensively for other indications, and theafety of most of them is supported byxtensive long-term data.

The Table summarizes the clinical trialshat were conducted on centrally active

FIGURE 2Role of norepinephrine in thedevelopment of hot flashes.

reedom RR. Pathophysiology and treatment ofenopausal hot flashes. Semin Reprod Med

005;23:117-25. Reprinted with permission ofhieme.

e

FEBRUARY 2007 Ame

rescription alternatives to HT. Most aremall-scale studies, but several large, ran-omized, double-blind, placebo-con-rolled trials have been completed. Thelasses of drugs that were evaluated includeSRIs, SNRIs, �-adrenoceptor antago-ists, and antidopaminergic drugs. Severalrugs that fall outside these groups haveeen examined also.

SRISSRIs have been evaluated extensively asreatment for menopausal mood symp-oms and could be considered rationalherapy for vasomotor menopausalymptoms, given the well-documentedole of serotonin in thermoregulation.esults from small-scale, short-termlinical trials have shown that the admin-stration of SSRIs may be effective in re-uction of the frequency and severity ofot flashes.10,49,52-57 These treatmentslso have been demonstrated to improveood, sleep, anxiety, and QOL in meno-

ausal women and in women who un-ergo estrogen-deprivation therapy forreast cancer.10,49,55 SSRIs also haveeen combined effectively with low-doseT. Results from a small-scale trial

howed that the combination of fluvox-mine (50 mg/d) with low-dose estrogen0.3125 mg/d) was significantly more ef-ective than estrogen alone in relievingot flashes and depressive symptoms inomen who had undergone oophorec-

omy (P � .036).58 However, it should beoted that clinical results for SSRIs areot uniformly positive. Results from atudy of fluoxetine and citalopram (eachitrated to a maximum dose of 30 mg/d)ndicated no significant benefit of eitherrug vs placebo in relieving hot flashes inostmenopausal women.59

Variability in clinical trial results for SS-Is may be related to the selectivity of dif-

erent agents in this class for the serotonins the norepinephrine transporter. Be-ause both neurotransmitters are thoughto be involved in thermoregulation and theevelopment of menopausal vasomotorymptoms, it is reasonable to suggest thatctivity at both transporters may be moreffective than high selectivity for only 1 ofhem. Paroxetine is the SSRI with the high-
st activity at the norepinephrine trans-
rican Journal of Obstetrics & Gynecology 101

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orter,60 and it has been shown repeatedlyo be effective for the treatment of meno-ausal vasomotor symptoms.49,55,57 Inontrast, fluoxetine and citalopram haveuch lower affinities for the norepineph-

ine transporter,60 and each of these SSRIsas been shown to have modest or variablefficacy in decreasing the frequency or se-erity of hot flashes vs placebo.10,53,59

Although SSRIs generally are well tol-rated, their use may be limited by sexualysfunction that may occur in as many as0% of women who are treated.61 Treat-ent with SSRIs also may be associatedith weight gain,62 which may decrease

dherence to potentially effective ther-py. The use of the lowest effective dosesan reduce the frequency of their adverseffects.56,62

EROTONIN-NOREPINEPHRINEEUPTAKE INHIBITORS

ecause norepinephrine and serotoninre both involved in the development ofenopausal symptoms, it is plausible to

xpect that an agent that is designed to

FIGURE 3In the premenopausal state, estrogthermoregulatory response (periph

n the menopausal state, estrogen concentrationsesponse to external thermal stimuli. In the abs

odulate these systems might be effec- 1


ive in reducing the frequency and sever-ty of these symptoms. Although resultsrom large-scale, long-term clinical stud-es are lacking, results from smaller-cale, well-controlled trials support these of agents in this class.63-68 Evans etl67 have demonstrated that the SNRIenlafaxine (dosed at 75 mg/d) was sig-ificantly superior to placebo in decreas-

ng interference by hot flashes with activ-ties of daily living in a 12-week trial thatncluded 80 menopausal women. Over-ll, venlafaxine decreased hot flash scoresrom baseline by 51% vs 15% for pla-ebo. Venlafaxine did not decrease hotash severity significantly in these pa-

ients. Nevertheless, 93% of women onenlafaxine planned to continue treat-ent after the study concluded. Loprinzi

t al64 have demonstrated that treatmentith venlafaxine for 4 weeks significantlyecreased the combined frequency andeverity of hot flashes in postmenopausalomen who did not want to take HT be-

ause of a history of breast cancer or con-ern about malignancy. In this study of

s stabilize the thermoregulatory setl vasodilation or constriction) to ex

decreased, and the set point is unstable, whiche of pharmacologic intervention, the set point r

91 patients (50 women received pla- o

FEBRUARY 2007

ebo, and 49, 43, and 49 women werereated with venlafaxine 37.5, 75.0, or50.0 mg/d, respectively), median hotash scores (a combination of frequencynd severity) were reduced from baseliney 27%, 37%, 61%, and 61%, respec-ively (P � .001 for the difference be-ween all venlafaxine treatment groupss placebo). Recently presented resultsave shown that a metabolite of ven-

afaxine is also effective in animal modelsf hot flashes, but its efficacy has yet to bevaluated in clinical trials.39

The efficacy of venlafaxine in reducingot flash activity must be balancedgainst possible adverse effects (tempo-ary nausea, decreased appetite, dryouth, sleeplessness, and constipation)

hat are seen with this drug.64-66 Patientsho are treated with venlafaxine may

lso experience sexual dysfunction.69

DDITIONAL NONHORMONALHERAPIESeuroactive agents from several other

lasses have been used for the treatment

oint, which results in a normalnal thermal stimuli.

ults in an altered vasodilatory thermoregulatoryjusts.7

en pera ter

are resenc ead

f hot flashes in menopausal women. Re-

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ults from a small-scale, short-term con-rolled clinical trial have demonstratedhat the anticonvulsant gabapentin (ti-rated up to 2700 mg/d) is significantly

ore effective than placebo in the reduc-ion of composite scores that reflect therequency and severity of hot flashes.70

his study of 59 women indicated thatabapentin 900 mg/d decreased hot flashrequency by 45% and the compositecore by 54% (P � .002 and P � .01 vslacebo, respectively). Loprinzi et al64

valuated gabapentin (titrated to 900g/d) in 20 women with a history of

reast cancer who did not want HT. Inhis small study, gabapentin decreasedhe frequency of hot flashes from base-ine by 66%.

In a large-scale, randomized, double-lind, placebo-controlled multiinstitu-ional trial, Pandya et al71 examined thefficacy of 2 doses of gabapentin (300g/d and 900 mg/d) in women with

reast cancer. Gabapentin treatment re-uced both the frequency and severity ofot flashes compared with placebo forhe higher dose only. At 900 mg/d, therequency of hot flashes dropped by 41%nd 44% at weeks 4 and 8, respectively,ignificantly greater than placebo (18%,

� .0001; 15%, P � .0002). After 4eeks of treatment, severity of hotashes had decreased by 49% for the00-mg/d group compared with 21% forhe placebo group (P �.0001). Hot flasheverity was also significantly reduced af-er 8 weeks of treatment (P � .007), buto further decrease was seen from theeek 4 measures (46% decrease fromaseline for the 900-mg/d group; 15%ecrease for placebo group). Slightlyore subjects in the gabapentin groups

han in the placebo group withdrewrom the study because of side effects; the

ost common side effect that was citedas somnolence.Adverse events (which include som-

olence, dizziness, rash, and peripheraldema) have resulted in the discontinu-tion of therapy by approximately 15%f patients who received this antiepilep-ic drug for the treatment of menopausalasomotor symptoms.72 Clinical experi-nce has indicated that the use of thisedication in some populations can also

ead to weight gain. e

Clonidine is an �-adrenoceptor antag-nist that was developed for the treat-ent of hypertension. Results from a

umber of small-scale studies of meno-ausal women and women who were be-

ng treated with tamoxifen have demon-trated modest efficacy for thisgent.73-79 Clonidine must be used withare because it is a potent antihyperten-ive. Nevertheless, results from 1 con-rolled study indicated no adverse hemo-ynamic effects of a 0.1-mg/d orallonidine dose in women who experiencedamoxifen-associated hot flashes.79 Theverall tolerability of oral clonidine iselatively poor, with a 40% discontinua-ion rate because of adverse eventsmong 10 women who were treated forenopausal symptoms.78 A transdermal

lonidine (0.6 mg transdermal therapeu-ic system) preparation has better toler-bility than the oral drug,80 but it ap-ears to have very limited usefulness forhe treatment of hot flashes because itrovides only a 10% reduction fromaseline in symptom severity.77 A second-adrenoceptor antagonist, methyldopa,lso has been examined in 2 small tri-ls.81,82 Both studies found that methyl-opa was more effective than placebo ineducing hot flashes, but in other studies,he drug has been found to have seriousotential side effects that include re-uced blood pressure, positive Coombsest, hemolytic anemia, and liver disor-ers.8

Veralipride, a benzamide derivativentidopaminergic drug, has been testedn small trials, mainly outside the Unitedtates.83-89 At a dose of 100 mg/d, it haseen shown to reduce the frequency andeverity of hot flashes in postmeno-ausal women and women who receiveonadotropin-releasing HT for menor-hagia or endometriosis. However, sideffects of veralipride included increasesn prolactin levels and galactorrhea.

Several additional agents have beenhe subjects of single trials. Mirtazapinea tetracyclic piperinoazepine analog ofianserin with activity at histaminergic,

erotonin, and �2-adrenoceptors) haseen shown to be effective for the treat-ent of hot flashes in an open-label

tudy that enrolled 22 subjects. How-
ver, 18% of the women in this trial with- f
FEBRUARY 2007 Ame

rew because of intolerable adversevents (excessive somnolence, dryouth, headache, flu-like symptoms,

nd muscle ache).90 The monoamine ox-dase inhibitor moclobemide was exam-ned in a small (n � 28) randomized,ouble-blind, placebo-controlled trial.91

oclobemide was tested at 2 doses, 150g/d and 300 mg/d, in the 5-week trial.he 150-mg/d group showed the greatestecrease in hot flash severity score, with a9.8% reduction from baseline com-ared with 24.4% for placebo. Propran-lol, a potent beta-1 and beta-2 adrener-ic antagonist, was tested in 25erimenopausal women.92 A 40-mgose given 3 times daily was no more ef-

ective than placebo at controlling hotashes.In its 2004 position statement, theorth American Menopause Society

ecommended venlafaxine, paroxetine,uoxetine, or gabapentin for womenith moderate to severe vasomotor

ymptoms who have concerns about orontraindications for HT.8 The state-ent described clonidine and methyl-

opa as having “only moderate efficacyombined with a relatively high rate ofdverse events.” An evidence-based re-iew published as part of the Nationalnstitutes of Health 2005 State-of-the-cience Conference on Management ofenopausal Symptoms made similar

ecommendations.93 The review con-luded that venlafaxine and paroxetineere the most effective of the newer an-

idepressants for the treatment of hotashes but added a caveat that parox-tine may interfere with tamoxifen in pa-ients with breast cancer. Citalopram

ay be effective for women whose con-ition does not respond to venlafaxine.abapentin was also considered effec-

ive.For all drugs, the reviews of both theorth American Menopause Society andational Institutes of Health recom-ended doses at the low end of the

anges that were tested in clinical trialsTable).8,93 The SSRIs/SNRIs effectivelyeduce numbers of hot flashes at dosesower than those that are used for anti-epressant therapy, and lower doses aressociated with fewer and milder side ef-
ects. The North American Menopause

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ociety specifically recommended ven-afaxine at 37.5 to 75 mg/d, paroxetine at2.5 to 25 mg/d, and fluoxetine at 20g/d, starting at lower doses and in-

reasing after 1 week. SSRIs and SNRIsave been approved for long-term use inatients with mood disorders (major de-ressive disorder and anxiety disorders);

t is well-known that relief from moodisorder symptoms may not occur untilreatment has continued for 4 to 8 weeks.owever, time-to-onset of efficacy and

uration of treatment have not been es-ablished in patients who are treated forasomotor symptoms. The reports ofoth the North American Menopauseociety and National Institutes of Healthecommended tapering the dose at theermination of treatment to minimizeosttreatment emergent adverse events,hich may be similar to treatment emer-ent adverse events.

OMMENThe physiologic mechanisms underlyingenopausal vasomotor symptoms are

till not completely understood, but anncreasing body of evidence links theseymptoms to an alteration in hypotha-amic thermoregulation and changes ineuromodulatory systems that arevoked by decreased levels of circulatingstrogen. Understanding what is knownbout the probable roles of norepineph-ine and serotonin in menopausal vaso-otor symptoms and how their actions

re influenced by nonhormonal thera-ies may help physicians when they dis-uss these treatment options with theiratients.Although no current treatment forenopausal vasomotor symptoms is

deal, neuroactive agents that interactith both norepinephrine and serotonin

ystems would appear to be a rationalhoice for treatment, given the involve-ent of both of these amines in thermo-

egulation. These agents have some un-esirable adverse effects and may havether actions that are unrelated to meno-ausal vasomotor symptoms. An idealreatment should be directed at the ther-

oregulatory dysfunction that gives riseo these symptoms and has minimal un-
anted effects in the body. It should be 1

rally bioavailable, safe, and have lowotential for interactions with otheredications that are likely to be taken byiddle-aged and older women.Many menopausal women experience

roubling symptoms that can include hotashes, night sweats, mood changes, andleep disturbances. These symptoms areelieved to be related to a dysfunction inNS thermoregulatory circuitry. Forany years, HT has been the mainstay of

reatment for menopausal vasomotorymptoms, and results from clinical tri-ls have demonstrated its efficacy repeat-dly. Recent concerns about long-termafety of standard-dose HT haverompted careful reanalysis of the risksnd benefits that are associated with thisherapy and heightened interest in otherreatments for menopausal vasomotorymptoms. Treatment of these symp-oms with either SSRIs or SNRIs is sup-orted by results from multiple well-ontrolled clinical trials. Less evidenceupports the use of other drugs (eg, gaba-entin, clonidine). An unmet need exists

or safe and effective therapeutic optionshat directly target thermoregulatory

echanisms that underlie menopausalymptoms for women who want treat-

ent but who prefer to avoid HT. Thevailability of new therapies with risksnd benefits clearly defined by resultsrom well-designed clinical trials has theotential to allay safety concerns that aressociated with the current treatmentsor menopausal vasomotor symp-oms. f

CKNOWLEDGMENTthank Dr Mary E. Hanson for assistance in thereparation of this manuscript.

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