Chapter  120:  Management of Menopause-Related Symptoms

Vasomotor Symptoms

Four studies from four population-based cohorts evaluated the association between vasomotor symptoms and menopausal stage, including three rated good-quality^{46, 51, 53}and one fair.²⁶ Women transitioning from premenopause to either perimenopause or postmenopause had increased vasomotor symptoms in the three good-quality studies.^{46, 51, 53}

The prevalence of hot flashes was reported in 33 cross-sectional studies.^{25, 27, 33, 35–37, 40, 48, 60, 62, 64, 66–67, 69–76, 78–85, 87–90} Prevalence rates ranged from 14 percent to 51 percent for premenopausal women, were approximately 50 percent for perimenopausal women, and between 30 percent to 80 percent for postmenopausal women, depending on the age and population studied. In one study, approximately 29 percent of women age 60 years reported hot flashes, suggesting only a modest decline in frequency with increasing time from menopause.⁶⁶

Vaginal Dryness

Vaginal dryness was associated with menopause, and became more common with the transition from premenopause to postmenopause, in the one good-quality cohort study examining this relationship.⁵³ Thirteen cross-sectional studies^{37, 40, 48, 69, 71, 72, 74–76, 80, 83–85} reported prevalence rates ranging from 4 percent to 22 percent for premenopausal women, 7 percent to 39 percent for perimenopausal women, and 17 percent to 30 percent for early postmenopausal women. Two cross-sectional studies showed either no association,⁸⁴ or a weak association,⁸³ between vaginal dryness and menopausal stage.

Sleep Disturbance

Three cohort studies evaluated the impact of menopausal status on sleep; two were rated good-quality^{46, 53} and one fair.²⁶ In the good-quality studies, women had more difficulty sleeping as they progressed through the menopausal stages,^{46, 53} and sleeping difficulty was associated with the presence of hot flashes.⁵³ The fair-quality study reported no association.²⁶

Eighteen cross-sectional studies evaluated the prevalence of sleep disturbance at different menopausal stages.^{25, 35–38, 48, 60, 69, 78–82, 84, 85, 87, 90, 92} Of these, eight reported prevalence rates ranging from 16 percent to 42 percent for premenopausal women, 39 percent to 47 percent for perimenopausal women, and 35 percent to 60 percent for postmenopausal women (including women with either surgical or natural menopause and hormone therapy users).^{37, 60, 78, 80–82, 85, 90} Some studies,^{79, 82, 87} but not others,^{38, 90} reported an association between hot flashes and sleep disturbance. When hot flashes/night sweats and insomnia were considered together in one study, 27 percent of premenopausal women, 46 percent of perimenopausal women, and 38 percent of postmenopausal women reported disturbances.²⁵

Four cross-sectional studies reported increased adjusted odds ratios for difficulty sleeping for menopausal women compared to premenopausal women^{37, 48, 69, 92} In one study, an age-adjusted significant correlation between sleep problems and menopausal status was reported, but increases among perimenopausal and postmenopausal women were small, and social class was a stronger predictor.⁶⁹ A factor analysis of sleep-related problems found sleep was not associated with menopausal status.⁸⁴ In another study, sleep disordered breathing increased across the menopausal stages after multivariate adjustment and stratification by BMI and age.⁹²

Mood Symptoms

Fourteen studies from 11 cohorts evaluated the impact of menopausal stage on mood.^{20, 24, 26, 28–30, 41, 44, 47, 51, 54, 55, 63, 68} Of these, seven were rated good-quality,^{29, 41, 47, 51, 54, 55, 68} four fair,^{20, 26, 28, 63} and three poor. ^{24, 30, 44} Symptoms included anxiety,²⁹ depression,^{20, 24, 28–30, 41, 63, 68} dysphoric or negative mood,^{26, 54} and positive mood.⁵⁵ Development of a mental disorder,⁴⁴ psychological symptom reporting,⁵¹ and general mental health⁴⁷ were also assessed.

Twelve of the 14 studies, including five good-quality, four fair, and three poor, found no influence of menopausal stage on mood symptoms, development of a mental disorder, or general mental health.^{20, 24, 26, 28–30, 44, 47, 51, 54, 55, 63} Two good-quality studies demonstrated a change in mood symptoms with the menopausal transition.^{41, 68} A well-designed, nested case-control study of age-matched menopausal and premenopausal women from the Pittsburgh cohort found no differences between the groups in depression, anger, anxiety, or stress symptoms.⁹³

Twenty-four cross-sectional studies reported relevant data.^{22–24, 33, 35, 36, 48, 50, 60, 63, 64, 66, 67, 69, 70, 72, 76, 80–85, 90} The prevalence of depressed mood ranged from 8 percent to 37 percent for premenopausal women, 11 percent to 46 percent for perimenopausal women, 8 percent to 47 percent for women with natural menopause, and 8 percent to 38 percent for women with surgical menopause.^{23, 66, 67, 80, 85}

Cognitive Disturbances

No cohort studies longitudinally assessed cognitive symptoms. Eight cross-sectional studies showed no differences in the prevalence rates of memory or concentration problems by menopausal stage.^{37, 48, 67, 69, 80, 81, 84, 85}

Somatic Complaints

Somatic complaints were evaluated in four studies conducted among three cohorts rated good-quality^{46, 47, 53} or fair-quality.²⁶ Perimenopausal women had increased somatic symptoms compared to premenopausal women in one cohort.^{46, 47} Symptoms included back pain, severe tiredness, stiff or painful joints, bodily pain, and worse general health. Other studies reported reduced breast tenderness,⁵³ or no association with somatic or neuromuscular symptoms.²⁶

Fourteen of 18 cross-sectional studies evaluating changes in somatic symptoms showed no significant increases as women transitioned from premenopause to postmenopause in adjusted analytic models.^{36, 37, 48, 64, 66, 67, 69, 71, 72, 81–85, 87} Three studies showed slight increases in somatic symptoms during perimenopause that decreased during postmenopause,^{78, 89} or remained stable.⁶⁷ Another study showed significantly fewer somatic symptoms for women at menopause compared with those at premenopause.⁹⁰

Urinary Complaints

Three good-quality cohort studies evaluated the impact of menopausal stage on urinary symptoms.^{46, 53, 56} In one study, women who were perimenopausal at baseline were more likely to report leakage of urine two years later than women who remained premenopausal.⁴⁶ Two studies from the Melbourne cohort found no association of menopausal status with urinary symptoms.^{53, 56}

Fourteen cross-sectional studies^{37, 45, 48, 49, 56, 60, 67, 71, 75, 77, 84–87} provided relevant data. Prevalence rates of urinary incontinence or leakage ranged from 10 percent to 36 percent for premenopausal women, 17 percent to 39 percent for perimenopausal women, 14 percent to 36 percent for women undergoing natural menopause, and 18 percent to 36 percent for women undergoing surgical menopause.^{37, 46, 56, 67, 86}

Uterine Bleeding Problems

No studies meeting inclusion criteria addressed uterine bleeding problems, most likely because currently accepted definitions of menopause rely historically on changes in uterine bleeding.

Sexual Dysfunction

Sexual dysfunction was evaluated in two fair-quality studies from the Melbourne cohort.^{57, 58} Sexual function was variably measured and included decreased responsivity, decreased libido, and/or decreased frequency of sexual activity. In that cohort, women demonstrated decreases in some or all of the sexual parameters as they transitioned from early to late perimenopause or postmenopause.^{57, 58}

Thirteen cross-sectional studies, including one from the Melbourne cohort, also evaluated sexual function.^{22, 40, 42, 48, 61, 65, 66, 69, 83, 84, 86, 89} Five studies showed the prevalence of sexual disinterest, dysfunction, or discomfort to increase from premenopause to perimenopause to postmenopause,^{48, 61, 67, 69, 86} and four showed no change.^{40, 65, 84, 89}

Reduced Quality of Life

Four cohort studies addressed the impact of menopausal stage on quality of life, three rated good-quality^{47, 52, 59} and one poor.³⁰ Two studies from the Melbourne cohort had conflicting results.^{52, 59} One study showed declines in well-being across progressive menopausal stages (lowest for the one to two years postmenopause) that improved when women were more than two years postmenopause.⁵² A second study showed increased well-being from early to late perimenopause and postmenopause.⁵⁹ In another good-quality study, women who remained perimenopausal over a two year follow-up period reported significant decreases in quality of life compared to women who remained premenopausal, although significant decreases were not reported by women in other stages.⁴⁷ A poor-quality cohort study found that well-being was not associated with change in menopausal status.³⁰

Three cross sectional studies also evaluated quality of life.^{22, 34, 74} Satisfaction with life,²² and impaired functioning³⁴ did not vary with menopausal stage in multivariate regression modeling of data from the Massachusetts Women's Health Study. In another study, various aspects of general well-being were lower among postmenopausal women compared to premenopausal women.⁷⁴

Race and Ethnicity

Two cohort studies^{38, 41} addressed the influence of race and ethnicity on menopausal symptoms, while many adjusted for it in multivariable models. Depression was reported more often among African American women compared to Caucasian women,⁴¹ and sleep difficulties were reported more often among Caucasian and Hispanic women and less often among African American, Chinese, and Japanese women.³⁸

Seven cross-sectional studies conducted in the large SWAN cohort also evaluated symptoms by race or ethnicity.^{33–37, 39, 70} In SWAN, vasomotor symptoms were reported more often among African American women and less often among Hispanic, Chinese, and Japanese women compared with Caucasian women.^{33, 37} Japanese, Chinese, African American, and Hispanic women reported fewer mood symptoms compared to Caucasian women,^{33, 35, 36} although “impaired social function” was reported among Hispanic women in two studies^{34, 70} and among African American women in one study.³⁴ Hispanic women also reported more bodily pain than Caucasian women.³⁴ A cross-sectional study conducted outside the SWAN cohort found that Mexican American women had similar prevalence rates of vasomotor symptoms and vaginal dryness as Caucasian women.⁷²

Age at Onset of the Menopause Transition

Long term studies evaluating menstrual cycles over many years among large cohorts of women showed the median onset of menstrual irregularity to begin between the ages of 45 and 47.5 years with a mean duration of the menopausal transition lasting 5 years.^94–96 Factors associated with earlier menopause include smoking,^97–99 shorter cycle length during menstruating years,¹⁰⁰ and shorter stature and leaner body weight.¹⁰¹ Factors associated with later age at menopause include higher gravidity or parity^{98, 99} and higher BMI.⁹⁹

A cross-sectional study reported increased rates of hot flashes among women with menopause prior to age 53 after adjustment for other factors.⁸⁸ Another found that earlier age of inception of perimenopause was related to a longer perimenopause stage.²¹

Body Mass Index (BMI)

Two good-quality cohort studies evaluated BMI and its effect on symptoms among menopausal or perimenopausal women and found that BMI was a significant predictor of urinary incontinence,⁵⁶ but not positive mood.⁵⁵ A cross-sectional study reported a slight increase in vasomotor symptoms (15 percent) among women with a BMI of 27 or greater, although, vasomotor symptoms were less common at the extremes of BMI.³⁷ Lower BMI was independently associated with increased hot flashes in another cross-sectional study.⁸⁸ Three cross-sectional studies^{22, 42, 74} found no significant differences for increased BMI. Other studies evaluating menopausal symptoms adjusted for BMI in multivariate models but did not report the contribution of BMI to symptoms.^{46, 47, 53, 92}

Surgical Versus Natural Menopause

Two good-quality^{29, 56} and one fair-quality cohort studies⁶³ reported data for women with surgical menopause. The Ohio Midlife Women's Study found that hysterectomy was not a predictor of anxiety or depression.²⁹ In contrast, a community-based study of women in Manitoba, Canada reported that women with hysterectomies had increased odds of depression.⁶³ In the Melbourne Women's Midlife cohort, surgical menopause was not a significant predictor of urinary incontinence.⁵⁶ Other symptoms were not addressed in these studies.

Sixteen cross-sectional studies reported symptoms among women with surgical and natural menopause.^{30, 38, 45, 48, 56, 63–66 70, 72, 73, 80, 86, 89, 90} Four studies showed no significant differences in vasomotor symptoms,^{48, 70, 80, 90} and three studies showed slightly higher rates of vasomotor symptoms among women with surgical menopause (seven percent to eight percent higher).^{64, 66, 73} Vasomotor symptoms were similar among Japanese and Canadian women with surgical and natural menopause in another study.⁷⁰ Three studies evaluated vaginal dryness; two showed similar rates,^{48, 72} and one reported a nine percent higher prevalence among women with surgical compared to natural menopause.⁸⁰ One cross-sectional study found no differences in rates of sexual dysfunction by type of menopause,⁴⁸ and another showed higher rates of urinary incontinence (36 percent vs. 22 percent) among women with surgical menopause.⁸⁶

The prevalence of anxiety and depression was evaluated in four cross-sectional studies,^{66, 70, 80, 89} and two showed higher prevalence rates among women with surgical menopause.^{66, 80} In a cross-sectional study from the Massachusetts Women's Health Study evaluating depression, women who had undergone surgical menopause in the previous three months were twice as likely as the rest of the cohort to have elevated depression scores.²⁴

Depression

The interaction of baseline depression with menopausal stage and/or transition and the presence or absence of symptoms was not evaluated in any cohort study. A cross-sectional study reported that prior anxiety or depression did not predict menopausal symptoms.⁴⁸ One other cross-sectional study evaluating menopausal symptoms adjusted for depression in a multivariate model but did not report the contribution of depression to symptoms.⁹²

Smoking

Three good-quality studies from the Melbourne Women's Midlife cohort examined the association of smoking status with mood symptoms and urinary incontinence.^54–56 In this cohort, current smoking was associated with negative mood,⁵⁴ but not positive mood,⁵⁵ and was not evaluated as an interaction term with menopausal transition or stage. Smoking was not a significant predictor of urinary incontinence.⁵⁶ Two good-quality studies adjusted for smoking in multivariate models, but did not report any data for this variable.^{46, 47}

Five cross-sectional studies provide data on smoking and menopausal symptoms.^{35, 37, 48, 62, 88} Two studies showed no association between smoking and menopausal symptoms,^{37, 62} one reported that smoking was associated with psychological distress but did not evaluate smoking as an interaction term,³⁵ and another showed that smoking at anytime in the past predicted greater vasomotor symptoms during menopause.⁴⁸ Another study reported no association between hot flashes and smoking, but identified higher rates of vasomotor symptoms among thin smokers than among thin non-smokers.⁸⁸ Other studies evaluating menopausal symptoms adjusted for smoking status in multivariate models but did not report the contribution of smoking status to symptoms^{39, 74, 92}

Estrogen

Three recent good-quality systematic reviews and meta-analyses of randomized controlled trials of estrogen, alone (unopposed) or combined with progestin or progesterone (opposed), describe benefits and harms of various forms, doses, and regimens for treating menopausal symptoms. These include a Cochrane review of trials of oral estrogen for hot flashes,^{16, 102, 103} a meta-analysis of trials of oral conjugated equine estrogen (CEE) and oral and transdermal estradiol for hot flashes,^{15, 104} and a review of commonly used types of estrogen for several menopausal symptoms.¹⁵ Trials were conducted predominantly in the U.S. or western Europe and recruited participants from primary care or gynecology practices. Most trials focused on healthy menopausal women in their early 50s with baseline symptoms that varied by study. All trials were double blind, of 12 weeks duration or more, and rated good or fair quality.

Vasomotor symptoms. The Cochrane meta-analysis indicated a significant reduction in frequency of weekly hot flashes for oral estrogen compared to placebo with a pooled weighted mean difference of -17.9 hot flashes per week (95% confidence interval [CI], -22.9 to -13.0; nine trials), equivalent to a 75.3 percent reduction in frequency (95% CI, 64.3 percent to 82.3 percent).¹⁶ Severity of symptoms was also significantly reduced compared to placebo (odds ratio [OR] 0.13; 95% CI, 0.07 to 0.23; 13 trials). Differences between types of estrogens were not determined, although trials of estradiol and CEE predominated. The review also found that the reduction in weekly hot flash frequency was similar for opposed and unopposed estrogen regimens compared to placebo (opposed: -19.9 per week; 95% CI, -26.7 to -12.6; three trials; unopposed: -14.7; 95% CI, -20.1 to -8.7; six trials). Symptom severity seemed to be better treated by opposed (OR 0.10; 95% CI, 0.06 to 0.19; 10 trials) than by unopposed estrogen (OR 0.35; 95% CI, 0.22 to 0.56; four trials), although heterogeneity of trials could also explain this difference.

Hot flash frequency, severity, or both improved in nine of 10 trials of oral estradiol and in all 11 trials of transdermal estradiol compared to placebo in a review of these agents.¹⁵ The pooled weighted mean differences in hot flashes were -16.8 per week (95% CI, -23.4 to -10.2; five trials) for oral estradiol, and -22.4 per week (95% CI, -35.9 to -10.4; six trials) for transdermal estradiol. Results were similar when opposed and unopposed regimens were considered separately.¹⁵ All eight trials of oral CEE reported statistically significant improvements in hot flash frequency, severity, or both compared with placebo. One trial of CEE that provided data comparable to the estradiol meta-analyses reported a mean reduction of -19.1 hot flashes per week (95 percent CI, -33.0 to -5.1). Four trials comparing estrogen agents head-to-head (CEE compared with oral or transdermal estradiol) indicated improved number and severity of hot flashes for all treatment groups with no significant differences between them (pooled weighted mean difference in hot flashes -0.3; 95 percent CI, -3.4 to 2.7; three trials).

In a review of 32 trials of estrogen for treatment of vasomotor symptoms, all but five were less than one year in duration and only three trials enrolled more than 500 participants, limiting evaluation of adverse effects.¹⁵ Trials reported multiple specific adverse effects including atypical bleeding and endometrial hypertrophy, nausea and vomiting, breast tenderness, headache, weight change, dizziness, venous thromboembolic events, cardiovascular events, rash and pruritus, cholecystitis, liver effects, and other adverse events. These outcomes were reported unevenly across studies and could not be combined in summary statistics. Trials included in the Cochrane review indicated similar adverse effects with breast tenderness and uterine bleeding most commonly reported.¹⁶

Urogenital symptoms/sexual dysfunction. In a systematic review of good and fair-quality trials of a variety of estrogen agents, urogenital symptoms improved in eight of nine trials, and sexual function (including pain during intercourse and responses to questionnaires) in eight of 11 trials.¹⁵ Vaginal forms of estrogen were evaluated in five trials. In a placebo controlled trial, vaginal dryness and pain during intercourse improved with use of the estradiol intravaginal ring compared to placebo.¹⁰⁵ A trial of the estradiol intravaginal ring and oral estradiol reported improved vaginal dryness, involuntary loss of urine, and pain during intercourse for both groups.¹⁰⁶ Head-to-head trials comparing the intravaginal estradiol ring with CEE vaginal cream among women with signs and symptoms of urogenital atrophy indicated that the two agents were comparable for relief of vaginal dryness and pain during intercourse, resolution of atrophic signs, improvement in vaginal mucosal maturation indices, and reduction in vaginal pH.^{107, 108} Similar findings were reported in a trial of the estradiol vaginal tablet and CEE cream.¹⁰⁹

Four placebo controlled trials of transdermal estradiol indicated improvements in some, but not all, urinary and sexual symptoms. Two trials reported improvements in responses to the McCoy Sex Scale Questionnaire compared to placebo,^{9, 110} although, another trial indicated no differences for symptoms of vaginal discomfort, loss of libido, and incontinence.¹¹¹ Another trial of transdermal estradiol indicated improvement in vaginal dryness, but not pain during intercourse, frequent urination, dysuria, stress incontinence, and nocturia, compared to placebo.¹¹²

A trial of oral CEE reported significantly improved vaginal dryness and urinary frequency, but no significant improvement on six other items related to sexual function on a General Health Questionnaire compared to placebo.¹¹³ A trial comparing oral CEE and transdermal estradiol indicated that the majority of women reported either no change or improvements in vaginal dryness and itching, pain during intercourse, and urinary pain and burning in all treatment groups with no major differences between groups.¹¹⁴ All treatment groups demonstrated improved vaginal cytology, measured by the maturation index, with the biggest improvement in the higher dose estradiol group (0.1 mg/day).

Sleep disturbance. Improved measures of sleep were specifically reported in three trials included in the systematic review.¹⁵ Transdermal estradiol provided significant improvements in sleep quality, sleep onset, and decreased nocturnal restlessness and awakening compared to placebo.¹¹⁵ In a subanalysis of the Women's Health Initiative (WHI) that considered women ages 50 to 54 years old who reported moderate to severe vasomotor symptoms at baseline, there was a positive effect on sleep disturbance with CEE compared to placebo.¹¹⁶ In contrast, a trial of CEE in women with hot flashes and nighttime awakening at baseline indicated improvement in menopausal symptoms and measures of psychological well-being, but not in parameters of sleep quality such as total sleep time, sleep onset time, number of awakenings, and REM sleep duration compared to placebo.¹¹⁷

Mood symptoms. Thirteen trials of estrogen reporting mood and depression outcomes met eligibility criteria (Table 5, Appendix 6-2), including three trials rated good-quality,^118–120 four fair,^121–124 and six poor.^125–130 Trials compared placebo with CEE,^{119, 121, 124, 126, 128} oral estradiol,^{120, 122, 125} transdermal estradiol,^{118, 126} piperazin oestrone sulphate,^{129, 130} and estropiate.¹²⁷ Head-to-head comparisons included estradiol and estradiol valerate,¹²³ CEE and clonidine,¹²⁸ CEE and raloxifene,¹¹⁹ and estradiol and raloxifene.¹²⁰

Two of the four good and fair-quality placebo controlled trials reporting between group differences found improved depressive symptoms among women using transdermal estradiol¹¹⁸ and oral estradiol with norethindrone acetate.¹²² No differences were found in trials comparing placebo with CEE/medroxyprogesterone acetate (MPA)¹²¹ or placebo with CEE.¹¹⁹ There were no differences in symptoms when comparing estradiol with estradiol valerate¹²³ and estradiol with raloxifene.¹²⁰ Another trial indicated improved anxiety with raloxifene vs. CEE, but no differences in depressed mood.¹¹⁹

Reduced quality of life. In a systematic review,¹⁵ four trials of transdermal estradiol,^{112, 131–133} two trials of oral estradiol,^{122, 134} and one trial of esterified estrogens¹³⁵ indicated improved health related quality of life and well-being compared to placebo, as measured by various instruments. In a subanalysis of the WHI that considered women ages 50 to 54 years old who reported moderate to severe vasomotor symptoms at baseline, there was no effect on health-related quality of life measures on the RAND 36-item Health Survey, despite significant improvements in vasomotor symptoms.¹¹⁶ A head-to-head comparison of CEE vs. transdermal estradiol utilizing the Menopause Specific Quality of Life Questionnaire indicated improvement in all areas with no significant differences between groups.¹³⁶

Progestin/progesterone

A total of 244 abstracts were identified and five randomized controlled trials met inclusion criteria (Table 6),^137–141 including one rated good-quality,¹³⁷ one fair,¹³⁸ and three poor.^139–141 Studies included transdermal progesterone,^{137, 138} intramuscular progesterone,¹³⁹ medroxyprogesterone acetate (MPA) tablet,¹⁴¹ and MPA injection.¹⁴⁰

Two trials of transdermal progesterone report conflicting results. A good-quality trial reported no differences between progesterone (32 mg/day) and placebo groups for vasomotor or somatic symptoms, mood, or sexual feelings as measured on previously validated instruments.¹³⁷ A fair-quality trial of a lower dose (20 mg/day) reported significant reductions in vasomotor symptoms, but not depression scores, with progesterone compared to placebo (83 percent vs. 19 percent; p<0.001).¹³⁸ A poor-quality trial of intramuscular progesterone described small differences between groups, however, the clinical significance of these are unclear.¹³⁹ Two poor-quality trials of MPA did not provide adequate statistical comparisons.^{140, 141}

None of the trials reported adverse effects.

Androgens

Testosterone. A total of 1,095 abstracts were identified from a search for trials of androgens that included testosterone and dehydroepiandrosterone (DHEA). Of these, 10 trials of testosterone met inclusion criteria including one rated good-quality,¹⁴² four fair,^{144–146, 148} and five poor^{143, 147–149, 151} (Table 7, Appendix 6-3). Major limitations of studies include few subjects, undefined inclusion and exclusion criteria, use of unclear outcome measures, and using open label rather than double blind methodology. Two additional studies were reported in abstract form and are included only in the evidence table (Appendix 6-3).^{152, 153}

Trials used methyltestosterone,^{142, 143, 145–149} testosterone undecanoate,^{150, 151} and transdermal testosterone.¹⁴⁴ All trials combined testosterone with estrogen and compared it head-to-head with estrogen, and two studies compared it with placebo.^{144, 149} Outcomes included sexual dysfunction,^{142, 144–146, 150, 151} hot flashes,^143–149 mood,^{144, 145, 147, 149, 150} sleep disturbances,^{143, 145, 147–149} vaginal dryness,^{143, 146–149} and quality of life.^{144, 145, 150}

Only one good-quality and two fair-quality trials reported statistical comparisons between testosterone/estrogen and estrogen or placebo groups.^{142, 143, 144} One trial indicated no differences between testosterone/estrogen and estrogen alone for hot flash severity, vaginal dryness, or sleep problems.¹⁴³ Sexual interest and responsiveness were improved with testosterone/estrogen compared to estrogen alone based on scores on the Sexual Interest Questionnaire in another trial.¹⁴² Sexual symptoms were also improved in a trial comparing testosterone/estrogen with placebo.¹⁴⁴

Adverse effects were reported in all 10 trials. Acne^{142, 143, 146, 148} and hirsutism^{146, 148} occurred significantly more often among women using methyltestosterone/estrogen than with estrogen alone. Adverse effects were not always separated by treatment group, making it difficult to determine which drug was responsible for the reported effect.^{144, 149–151}

Dehydroepiandrosterone (DHEA). One fair-quality¹⁵⁴ and one poor-quality¹⁵⁵ randomized controlled trial met inclusion criteria (Table 7, Appendix 6-4). Studies were small, lacked clear exclusion criteria,¹⁵⁵ and had high losses to follow up.¹⁵⁴

Trials used dehydroepiandrosterone (DHEA)¹⁵⁴ and dehydroepiandrosterone sulfate (DHEAS)¹⁵⁵ alone^{154, 155} or combined with transdermal estradiol.¹⁵⁵ No significant differences between DHEA and placebo were determined on any measures of symptoms including hot flashes, vaginal dryness, insomnia, depression, urinary difficulties, libido, concentration, dizziness, forgetfulness, irritability, aches, anxiety, headaches, and fatigue in the one trial reporting between group differences.¹⁵⁴

Adverse effects were reported for DHEA only and included paresthesia of an upper extremity.¹⁵⁴

Tibolone

A total of 162 abstracts were reviewed and 20 randomized controlled trials met inclusion criteria (Table 8, Appendix 6-5) including three rated good-quality,^156–158 four fair,^159–162 and 13 poor.^163–175 Four additional studies were reported in abstract form and are included only in the evidence table (Appendix 6-5).^176–179

Trials compared tibolone with estrogen alone,¹⁶⁹ estrogen combined with progestin or progesterone,^{158–160, 162, 163, 166, 170, 171, 173–175}or placebo.^{156, 157, 161, 164, 165, 167, 168, 172} Outcomes included hot flashes, sexual dysfunction, mood, uterine bleeding, somatic complaints, vaginal dryness, sleep disturbance, cognitive effects, urinary complaints, and quality of life.

Three good or fair-quality trials reported between group differences for tibolone and placebo.^{156, 157, 161} Results indicated improved hot flashes,¹⁵⁷ sleep,¹⁵⁷ and somatic complaints¹⁵⁶ with tibolone, but no differences between groups in Greene Climacteric Score,¹⁵⁶ quality of life,^{157, 161} or mood, energy, pain, social isolation, or urinary symptoms.¹⁵⁷

Four good or fair-quality trials reported between group differences for tibolone and estrogen alone or estrogen combined with progestin or progesterone.^{158–160 162} Two trials indicated improved hot flashes with estrogen compared to tibolone.^{159, 160} Sexual interest, drive, and/or performance were improved with tibolone compared to CEE/MPA in another trial.¹⁶⁰ No differences between groups were determined for several other menopause related symptoms.^{158–160, 162}

Uterine bleeding was increased with tibolone in four trials,^{157, 167, 168, 180} decreased in two,^{159, 167} and was not significantly changed in four others.^{158, 162, 163, 174} Uterine bleeding was dose related in two studies.^{168, 180} Adverse effects that occurred significantly more often among women using tibolone than placebo were reported in 16 of 20 trials and included body pain,^{156, 160, 163, 164, 166, 170, 174, 175} weight gain,^{156, 158, 160, 164, 166, 169, 175} and headache.^{156, 160, 163, 166, 167, 170} Four studies did not report adverse effects.^{162, 171–173}

Antidepressant drugs

A total of 184 abstracts were reviewed and eight randomized controlled trials met inclusion criteria including one trial rated good-quality,¹⁸¹ three fair,^{182, 183, 188} and four poor^184–187 (Table 9, Appendix 6-6). Trials used paroxetine,¹⁸¹ venlafaxine,¹⁸³ moclobemide,¹⁸⁸ and veralipride.^{182, 184–187} Most studies were limited by small sample sizes, short durations of follow-up, lack of follow-up data, inadequate descriptions of inclusion criteria, and, in one trial, lack of blinding.¹⁸⁷

Selective serotonin reuptake inhibitors (SSRIs). A good-quality trial of paroxetine reported statistically significant reductions in mean hot flash frequency and hot flash composite score at two doses compared with placebo.¹⁸¹ No differences were detected in sleep, depression, anxiety, sexual interest, disability, or side effects.¹⁸¹ A fair-quality trial of venlafaxine reported improvement on a single item measuring how significantly hot flashes interfered with daily activities compared to placebo, but no differences in hot flash frequency or severity as measured on daily diaries.¹⁸³ The venlafaxine group also had improved mood and vitality compared with placebo.¹⁸³ Other trials of SSRIs enrolled women with breast cancer and are described below.

Moclobemide. A fair-quality trial evaluating two doses of moclobemide showed reduced hot flash composite scores with moclobemide at both doses, although comparisons with placebo were not reported.¹⁸⁸ This trial was further limited by including only 30 participants and lasting only five weeks.

Veralipride. Veralipride, an antidopaminergic drug, was evaluated in five trials; one rated fair-quality¹⁸² and four poor-quality.^184–187 Two poor-quality trials comparing veralipride to placebo reported reduced rates of hot flashes with veralipride.^{184, 185} Of the two studies comparing veralipride to estrogen, a poor-quality trial found that veralipride had less benefit,¹⁸⁷ and a fair-quality trial found it to be equivalent.¹⁸²

In four of the five studies, the side effects of mastodynia and/or galactorrhea occurred more frequently in the veralipride group.

Other Drugs

A total of 51 abstracts were identified and 15 randomized controlled trials met inclusion criteria (Appendix 6-7). Trials used clonidine,^{128, 189–197} gabapentin,¹⁹⁸ methyldopa,^199–201 and Bellergal Retard.²⁰² Major limitations of trials include few subjects, lack of clear inclusion and exclusion criteria, high attrition or loss to follow up, no washout period in crossover trials, lack of data for pre-crossover comparisons, and short treatment duration.

Clonidine. Clonidine was compared to placebo in eight trials,^{189–195, 197} and compared to other active drugs in trials with lisuride, sodium valproate, transdermal estradiol,¹⁹⁵ and CEE and medrogestone^{128, 196} (Table 10). Two trials were rated fair-quality,^{189, 192} and eight were poor.^{128, 190, 191, 193–197} Outcomes included hot flashes, insomnia, and mood symptoms.

Of the trials for which pre-crossover statistics were provided or could be calculated, there were no statistically significant differences between clonidine and placebo in the improvement of hot flash symptoms.^{189, 191, 192} In the non-crossover placebo controlled trials, one trial reported that clonidine was more effective than placebo in reducing hot flash frequency and intensity,¹⁹⁵ and the other found no differences between groups in number of hot flashes, although women on clonidine were significantly more likely to report a decrease in subjective frequency, severity, and duration of hot flashes.¹⁹⁷ Of the 3 remaining crossover studies reporting only summary statistics,^{190, 193, 194} one trial demonstrated that clonidine was more effective than placebo in reducing the number of hot flashes and improving subjective hot flash measures.¹⁹³ Two head-to-head trials found that estrogen, not clonidine, effectively decreased the number of hot flashes and improved measures of depression and anxiety.^{128, 196} Two trials found no differences between clonidine and placebo in measures of psychological symptoms,^{191, 192} and one found no difference in frequency of insomnia.¹⁹²

Adverse effects were reported in six of 10 trials; dry mouth occurred more frequently in women taking clonidine than placebo,^{189, 191, 193} and blood pressure was not affected by clonidine.^{189, 190, 192–194, 197}

Methyldopa. Three crossover trials, two rated fair-quality^{200, 201} and one poor,¹⁹⁹ compared methyldopa with placebo (Table 11). All trials provided pre-crossover statistics regarding improvement in hot flash frequency and none found significant differences between groups. A fair-quality study reporting post-crossover data separately found that methyldopa was more effective than placebo in reducing the number of hot flashes and improving Visual Analog Scores after crossover.²⁰¹

All trials noted substantially more adverse effects with methyldopa than placebo. Fatigue or drowsiness, dizziness, and dry mouth occurred more often among women using methyldopa than placebo. One patient on methyldopa developed a lupus-like rash.²⁰⁰ No significant changes in blood pressure were noted,^{199, 201} however, one study reported orthostatic hypotension in one patient.²⁰⁰

Gabapentin. In a good-quality study comparing gabapentin to placebo, hot flash frequency and a composite menopause symptom score were significantly improved with gabapentin (Table 11).¹⁹⁸ No significant differences in mood, quality of life, Patient Global Impression of Change scores, and sleep quality were detected.¹⁹⁸

Gabapentin use reduced levels of albumin, total protein, total bilirubin, blood urea nitrogen, and platelets compared to placebo. Somnolence, dizziness, rash, and peripheral edema were reported for gabapentin but not placebo. Fifty percent of the gabapentin group and 28 percent of the placebo group reported at least one adverse event.

Bellergal. One poor-quality trial compared Bellergal Retard, a combination of 0.6 mg ergotamine, 40 mg phenobarbital, and 0.2 mg levorotatory alkaloids, with placebo (Table 11).²⁰ There were no statistically significant differences between Bellergal and placebo in measures of vasomotor symptoms, insomnia, nervousness, hyperirritability, headache, paresthesia, loss of libido, and dizziness.

Adverse effects were similar between groups and included dry mouth, dizziness, and sleepiness.

Phytoestrogens

A total of 195 abstracts were identified and 21 randomized controlled trials met inclusion criteria (Table 12, Appendix 6-8). Trials used dietary soy isoflavones,^203–213 soy isoflavone extracts,^214–218 other forms of phytoestrogens,^219–223 and phytoestrogens combined with other agents.²²⁴ Eight additional studies were reported in abstract form and are included only in the evidence table (Appendix 6-8).^225–232

Soy isoflavones—dietary. Dietary forms of soy isoflavones were compared to placebo in 10 trials (Table 12) that included soy powder,^{203, 204, 211, 213} cereal,²⁰⁵ drink,^{206, 212} diet,^{208, 211} flour,²⁰⁹ and tablets.^{207, 210} Of these, seven were rated fair-quality,^{203, 204, 206, 207, 209–212} and three poor.^{205, 208, 213} Outcomes included hot flashes, sleep, mood or depression, vaginal dryness, sexual symptoms, scores on symptoms scales, and single trials reporting palpitations, headaches, and general health.

Of the eight trials providing between group comparisons, one fair-quality and one poor-quality trial reported improved hot flashes with soy compared to placebo^{203, 204, 213} and six reported no differences.^{205, 206, 209–212} A fair-quality trial of soy powder reported improved hot flash frequency with soy compared to placebo (44 percent vs. 31 percent, p<0.01), but no differences between groups on the Kupperman Index.^{203, 204} A poor-quality trial of soy protein tablets indicated improved severity of hot flashes and improved hypoestrogenic symptoms score with soy, but no differences in number of hot flushes, night sweats, sleep disturbance, or general health score.²¹³ In most trials, hot flashes improved in both soy and placebo groups,^{203, 204, 206, 209–212} although in two trials rated poor-quality, the placebo group reported improved symptoms while the soy group did not.^{205, 208}

Soy isoflavones—extract. Soy isoflavone extracts were compared to placebo in five trials (Table 12), including four rated fair-quality,^{214–216, 218} and one poor.²¹⁷ Outcomes included hot flashes, cognitive tests, scores on the Greene Climacteric Index, and mood.

Of the three trials providing between group comparisons and hot flash outcomes, all reported improved hot flash frequency^{216, 217} or severity²¹⁸ with soy compared to placebo, and one trial reported no differences in frequency of night sweats.²¹⁸ The Greene Climacteric Scale score was improved with soy compared to placebo in one trial,²¹⁷ but not the other.²¹⁵ Performance on cognitive tests, including tests of memory, improved with soy compared to placebo in the two trials evaluating this outcome.^{214, 215} Mood was not improved with soy in one trial.²¹⁵

A trial reporting adverse effects of isoflavones indicated an increased rate of endometrial hyperplasia after five years of using 150 mg/day of isoflavone soy supplement.²³³

Other phytoestrogens. Phytoestrogens were compared to placebo in five trials (Table 12), including two rated fair-quality^{221, 223} and three poor.^{219, 220, 222} Trials included diet,²¹⁹ topical cream,^{220, 222} and genistein tablets.^{221, 223} One trial included a comparison group using estradiol and noresthisterone.²²¹ Outcomes included hot flashes in all trials, vaginal dryness, scores on menopausal symptom scales, mood, sexual symptoms, and energy level.

Three of five trials providing between group comparisons and hot flash outcomes reported improved hot flash severity²¹⁹ or score^{221, 223} with phytoestrogen compared to placebo. Two trials reported no differences compared to placebo in frequency and severity of hot flashes²²² or Kupperman Index score,²²³ and another indicated that the hot flash score was better with estradiol and noresthisterone than genistein.²²¹ Vaginal dryness was improved with phytoestrogen diet in one trial,²¹⁹ but there were no significant differences in overall symptom scores.²¹⁹ A trial of wild yam cream found no differences in mood, libido, or energy level.²²²

Combinations. A poor-quality trial of soy based isoflavones combined with C. racemosa (black cohosh) reported improved hot flush symptoms with treatment compared to placebo, as reported on a questionnaire.²²⁴

Complementary and Alternative Medicine

A total of 1,237 abstracts were identified and 28 randomized controlled trials met inclusion criteria (Table 13, Appendix 6-8). Trials used acupuncture,^234–236 Chinese herbs,^237–242 red clover,^243–248 black cohosh,²⁴⁹ combinations,²⁵⁰ other supplements,^251–259 manual therapies,²⁶⁰ and energy therapies.²⁶¹ Four trials were reported in abstract form and are included only in the evidence table (Appendix 6-8).^{227, 231, 262, 263}

Acupuncture. Four small trials compared a series of acupuncture treatments specific to menopausal symptoms with alternate nonspecific acupuncture procedures (Table 13).^{234–236, 264} Of these, one trial was rated fair-quality²⁶⁴ and three poor.^234–236 The fair-quality trial found no differences between groups in any measures,²³⁶ while a poor-quality study reported improved mood in the treatment group, but no differences in menopausal symptoms or well-being.²³⁵ A poor-quality trial compared acupuncture treatment specific to menopausal symptoms to both nonspecific acupuncture and estrogen and found a more pronounced improvement in hot flashes with estrogen than acupuncture.²⁶⁴

Chinese herbs. Three fair-quality trials^240–242 and three poor-quality trials^237–239 of Chinese herbs met criteria for this review. Five trials compared herbs against placebo^238–242 and two against CEE/MPA^{237, 242} (Table 13). Treatments included specific formulations of herbs,^{237, 238} ginseng,^{239, 241} dong quai,²⁴⁰ and an herbal remedy (pueraria lobata) combined with isoflavone.²⁴² Outcomes included hot flashes and other vasomotor symptoms, mood and depression, well-being and quality of life, memory, somatic symptoms, sexual symptoms, and general health. Studies were small, had short durations, and included highly selected populations.

A fair-quality trial comparing ginseng with placebo reported significant improvements for depression, well-being, and health scores on the Psychological General Well Being Index, but no differences in hot flashes or scores on other instruments.²⁴¹ Results of two other fair-quality placebo controlled trials indicated no differences between groups for menopausal symptoms,^{240, 242} well-being,^{240, 242} or rate of learning.²⁴²

Red clover. Red clover isoflavone tablets (Promensil and Rimostil) were compared against placebo in six trials (Table 13) including one rated good-quality,²⁴⁷ four fair,^{243–245, 248} and one poor.²⁴⁶ Outcomes included hot flashes and other vasomotor symptoms including measures from the Greene Climacteric Scale. One of five trials reporting between group comparisons indicated improved hot flashes with treatment compared to placebo,²⁴⁸ and no trials reported differences in scores on the Greene Climacteric Scale or symptom diary.^{243, 244, 246–248}

A good-quality meta-analysis of 25 trials of phytoestrogens for treatment of menopausal symptoms included an analysis of red clover using five of the six studies in this review.^244–248 Results of the meta-analysis indicated no significant differences in hot flash frequency between treatment and placebo groups (weighted mean difference -0.60; 95 percent CI, -1.71 to 0.51).¹⁸

Black cohosh. One fair-quality trial compared C. racemosa preparation (black cohosh) with estrogen and placebo (Table 13).²⁴⁹ Between group comparisons indicated improved hot flushes with estrogen vs. placebo only.

Combinations. A small poor-quality trial of a botanical formula (burdock root, licorice root, motherwort, dong quai, and wild yam) compared with placebo indicated no differences between groups in the number and severity of hot flashes (Table 13).²⁵⁰ Results indicated a significant decrease in the total number of other types of symptoms after three months of therapy for the botanical formula group compared to placebo (p<0.03).²⁵⁰

Other supplements. Nine trials evaluated effects of other forms of supplements including melatonin,²⁵¹ vitamin E,²⁵² kavakava,²⁵³ evening primrose oil with vitamin E,²⁵⁴ guar gum,²⁵⁵ vaginal moisturizer,^{256, 257} phospohlipid liposome injections,²⁵⁸ and S-adenosyl-L-methionine²⁵⁹ (Table 13). Of these, two trials were rated fair-quality^{253, 258} and seven poor.^{251, 252, 254–257, 259} Outcomes included hot flashes, mood or depression, vaginal dryness, and scores on symptom scales.

Between group differences for placebo controlled trials indicated improved symptoms with treatment compared to placebo for mood or depression (melatonin, S-adenosyl-L-methionine),^{251, 259} anxiety (kavakava, phospholipids liposomes),^{253, 258} and scores on symptom scales (phospholipid liposomes).²⁵⁸ No differences between groups were found for hot flashes (guar gum),²⁵⁵ mood or depression (kavakava),²⁵³ and scores on symptom scales (kavakava).²⁵³ In a poor-quality trial of evening primrose oil, hot flashes were significantly improved with placebo compared to treatment.²⁵⁴ A poor-quality trial comparing vaginal moisturizer against dienoestrol vaginal cream reported improved vaginal dryness with dienoestrol.²⁵⁶

Manual therapies. A fair-quality trial of low force osteopathic manipulation of the pelvis, spine, and cranium was compared against sham low force touch in similar areas (Table 13).²⁶⁰ After 10 weeks of therapy, results indicated improved hot flashes and nights sweats, urinary frequency, depression, and insomnia with treatment compared with placebo.²⁶⁰

Energy therapies. A poor-quality trial of women undergoing nine sessions of reflexology provided over 19 weeks resulted in no differences in severity of hot flashes and night sweats or measures of health and well-being compared to women receiving standard foot massages (Table 13).²⁶¹

Behavioral Interventions

A total of 436 abstracts were identified and eight randomized controlled trials met inclusion criteria (Table 14, Appendix 6-8). Trials consisted of exercise,^265–267 relaxation, ^268–270 low frequency sound wave audiotape,²⁷¹ and education interventions.²⁷² Of these, three trials were rated fair-quality,^{265, 267, 272} and five poor.^{266, 268–271} One additional trial was reported in abstract form and is included only in the evidence table (Appendix 6-8).²²⁶

Exercise. Two fair-quality studies evaluated the effects of aerobic exercise using comparison groups that underwent stretching activities²⁶⁵ or received usual care²⁶⁷ (Table 14). Outcomes included hot flashes and other vasomotor symptoms, mood and depression, cognitive function, sleep, well-being, and quality of life. Results of one trial indicated no differences in outcomes in the exercise group compared to the stretching group.²⁶⁵ A subset of women categorized as recently entering menopause showed improved memory in the aerobic vs. stretching group. ²⁶⁵ In a trial of exercise compared to usual care, exercisers showed significantly improved quality of life on the Nottingham Health Profile.²⁶⁷

Other Interventions. A fair-quality trial compared health education with usual care and found no differences between groups for measures of mood, health, vaginal dryness, or sexual relationships.²⁷² Knowledge of menopause increased in the intervention group, while the control group was more likely to attribute symptoms to menopause.²⁷² Other trials rated poor-quality due to limitations in methods and/or small numbers of subjects evaluated biofeedback, relaxation, paced respiration, and use of audiotapes (Table 14).