Wulf H. Utian, MD, PhD, DSc

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Quality of Life (QOL), a construct which has not yet achieved precise definition in the medical literature, nonetheless is a necessary outcome variable requiring measurement in determining comprehensive menopausal status in the clinical context or as part of pivotal regulatory 

 research. Current QOL measures are mostly symptom inventories or scores relating to specific life phases or diseases. 

We have reported on the Utian Quality of Life (UQOL) instrument. This is a brief instrument which measures QOL during the perimenopausal years through a 23-item questionnaire which demonstrates four separate intercorrelated domains. The UQOL with its simplicity of administration should be of practical value in clinical practice in evaluating QOL and changes in QOL in different communities and cultures. 

Unfortunately, at this time, no such validated tool has been used in clinical studies, although the UQOL is currently being tested in HRT trials. 

In the absence of definitive data, only speculation can be made as to whether HRT enhances QOL.

Articles

Quality of Life (QOL), a construct which has not yet achieved precise definition in the medical literature, nonetheless is a necessary outcome variable requiring measurement in determining comprehensive menopausal status in the clinical context or as part of pivotal regulatory trial research. Current QOL measures are mostly symptom inventories or scores relating to specific life phases or diseases.

Does HRT Enhance Quality of Life?

Many women experience       vasomotor symptoms at or around the time of menopause. Hot flushes and       night sweats are considered primary menopausal symptoms that may also be       associated with sleep and mood disturbances, as well as decreased       cognitive function. All of these symptoms may lead to social impairment       and work-related difficulties that significantly decrease overall quality       of life. Hot flushes have shown a great deal of variability in their       frequency and severity in women. In some women, hot flushes persist for       several months; in others, they may last for more than 10 years.       Traditionally vasomotor symptoms were reported to begin 5 to 10 years       prior to the cessation of the final menstrual cycle, corresponding with       the initial decline in circulating gonadal hormones; however, night sweats       in particular most often begin in perimenopause. The pathogenesis of hot       flushes has not yet been fully elucidated, but the circuitry involving       estrogen and neurotransmitters, norepinephrine and serotonin specifically,       are hypothesized to play a major role in the altered homeostatic       thermoregulatory mechanisms underlying these events.

Menopause-associated       vasomotor symptoms are associated with significant direct and indirect       costs. Overall costs of traditional pharmacotherapy or complementary and       alternative medicine modalities, including over-the-counter treatments and       dietary supplements, for managing menopause-related vasomotor symptoms are       substantial and include initial and follow-up physician visits and       telephone calls. Additional costs include laboratory testing, management       of adverse events, loss of productivity at work, and personal and       miscellaneous costs. Pharmacoeconomic analyses, including those that       consider risks identified by the Women's Health Initiative, generally       support the cost-effectiveness of hormonal therapy for       menopause-associated vasomotor symptoms, which have been the mainstay for       the management of these symptoms for more than 50 years. However, because       many women now want to avoid hormone therapy, there is a need for       additional targeted therapies, validated by results from controlled       clinical trials that are safe, efficacious, cost-effective, and well       tolerated by symptomatic menopausal women.


       Menopause is characterized by       physiologic and psychosocial changes in a woman's life. Menopause may be       associated with vasomotor symptoms (VMS; hot flushes [also referred to as       hot flashes] and night sweats), bone loss, urogenital atrophy, urinary       tract infections and incontinence, increased cardiovascular risk, somatic       symptoms, sexual dysfunction and decreased libido, and loss of skin       elasticity. VMS, and the sleep and mood disturbances that often result       from them, can have a significant negative impact on overall quality of       life (QOL) for a substantial number of women. The impact of VMS has gained       in importance as the lifespan of women has increased throughout the world       since women can expect to spend a significant portion of their lives after       menopause. This period should be a highly productive time for women, and       maintaining functional ability and a good QOL is of utmost importance.       Accordingly, it is important to understand the economic and QOL impacts of       menopausal VMS as well as the most recent pharmacoeconomic analyses of       different approaches to managing symptoms. Thus, the aims of this paper       are to briefly review the epidemiology of VMS, describe what is known       about the physiologic basis of these symptoms, and examine the global and       health-related quality of life (HRQOL) effects of VMS in women, with a       focus on psychosocial and economic impairments, and costs associated with       treatments.


       Recent US Census Bureau statistics indicate that approximately one third       of women are older than 50 years of age [1].       It is estimated that 75% of women in this age group will experience hot       flushes, a value supported by a recent longitudinal study of 454 women who       were followed from premenopause to postmenopause [2].       Thus, in the United States alone, there are approximately 40 to 50 million       women who experience hot flushes [1].       Worldwide, between 50% and 85% of women (approximately 360 million) older       than 45 years of age experience hot flushes [3].       The prevalence of hot flushes varies widely across populations and is       strongly influenced by culture and ethnicity. In the United States, the       Study of Women's Health Across the Nation (SWAN) surveyed more than 16,000       women and found that the prevalence of hot flushes was highest among       African Americans (46%), followed by Hispanics (34%), whites (31%),       Chinese (21%), and Japanese (18%) [4].       In other parts of the world, rates of hot flushes vary widely as well,       with the lowest prevalence observed in China (10%) and other Asian nations [5].       

Many attempts have been made to identify demographic characteristics       associated with a significantly increased risk of hot flushes. For many       years, low body mass index (BMI) and race were considered significant       predictors of VMS, with thin, white women believed to at the highest risk       for hot flushes. More recent findings have suggested that high BMI and       African American race are associated with a higher risk of VMS. This shift       may be related to better sampling of the general population by major       clinical trials because, traditionally, white middle-class women       participated in clinical trials that often did not include women from       other ethnic groups. The multiethnic SWAN not only demonstrated a link       between an elevated BMI (≥27 kg/m

) and hot flushes [4],       but an increased prevalence in African American women, as mentioned.       Ongoing studies continue to investigate potential predictors of hot       flushes. Smoking, maternal history, history of premenstrual complaints,       elevated basal core body temperature, low physical activity, low       socioeconomic status, and low levels of estrogen and high levels of       luteinizing and follicle-stimulating hormones prior to the menopausal       transition have all been associated with an increased risk of hot flushes [4,6-8].


       The timing and frequency of hot flushes have been reviewed by several       researchers [9]. SWAN       demonstrated that hot flushes occur earlier than previously believed and       may become less frequent and less intense as menopause progresses. SWAN       data indicated that VMS were more frequently reported by women in late       perimenopause with a relative risk for hot flushes at 1.0 during       premenopause (the 1 or 2 years prior to menopause), 2.06 during early       perimenopause (the early menopausal transition), 4.32 during late       perimenopause (the late menopausal transition), and 2.81 during       postmenopause [4]. The frequency       of hot flushes varies but tends to remain consistent for an individual [10].       Many women have hot flushes on a daily basis, some as frequently as every       hour, whereas others have VMS infrequently (i.e., weekly or monthly) [10].       The majority of women experience hot flushes for 6 months to 2 years, with       the highest number of women reporting symptoms during the first 2       postmenopausal years [9,10].       However, in another study, 26% of women reported having hot flushes for 6       to 10 years, whereas 10% have had VMS for more than 10 years [11].


       The cause of hot flushes has yet to be determined because of the limited       research focus in this therapeutic area. Hot flushes are believed to       result from the brain's response to diminished hormones and hormonal       fluctuations that occur during the menopausal transition. Ovarian hormones       have been shown to influence thermoregulatory mechanisms that regulate       temperature homeostasis in the hypothalamus. The neurotransmitters       serotonin and norepinephrine play a role in modulating core body       temperature, neurochemical messaging, and peripheral vasculature [12].       Kronenberg and colleagues were the first investigators to document       cardiovascular, temperature, hormonal, and autonomic parameters with hot       flushes and link them with thermoregulatory mechanisms [13],       with more recent mechanistic information published by Freedman [14]       and Deecher et al. [12].


Perceived QOL is difficult to measure and there is no universal       agreement on how it should be quantified. Objective measurements of health       status (often referred to as HRQOL) may not capture the patient's       perception of overall life satisfaction. QOL can be defined as a       reflection of an individual's belief about functioning and achievement.       HRQOL may be viewed as the individual's perception regarding her physical,       cognitive, and mental health as well as social situation [15].       Assessments of overall QOL for menopausal women must include consideration       of somatic symptoms (hot flushes, night sweats, urogenital atrophy),       psychological symptoms (depression, mood swings, irritability, anxiety),       and life circumstances (function in the workplace). Thus, overall QOL may       include four major factors: occupational, health-related, sexual, and       emotional [15]. Consideration of       HRQOL is also influenced by women's increased risk of multiple chronic       diseases associated with menopause, including osteopenia, osteoporosis and       related fractures, and cardiovascular disease [16].


VMS can have a significant negative impact on QOL in younger and       older women, contributing to physical as well as psychosocial impairment              (Table 

).       Becoming flushed and sweating profusely in a social or work-related       situation may cause extreme anxiety for many women and lead to social       isolation [17].

Although it is generally       accepted that VMS are troubling to many women and adversely impact their       QOL, these effects are difficult to quantify because of the many factors       that contribute to overall QOL satisfaction. For example, an objective of       the Women's Health Initiative (WHI) was to determine whether hormonal       therapy (HT) could reverse impaired HRQOL in 16,608 women aged 50 to 79       years. Results from this analysis indicated that estrogen plus       progesterone did not yield any significant benefits in any of the HRQOL       outcomes when compared with placebo over 3 years of follow-up [18].       However, this investigation did not examine global QOL in relation to VMS       as an a priori outcome, and the women studied were not only excluded if       the investigators felt they were having significant VMS that would       interfere with long-term study involvement, but were older than those who       typically have VMS and use HT. Another limitation was the use of a QOL       questionnaire that may have been inadequate for determining the global       impact of VMS. More recently, a new QOL scale has been designed       specifically for the perimenopausal population [19]:       The Utian Quality of Life (UQOL) Scale evaluates occupational, health,       emotional, and sexual QOL. This 23-item assessment should increase the       reliability of QOL measurement in perimenopausal and postmenopausal women.

The physiologic changes       associated with menopause often result in increased anxiety and stress.       These feelings may arise from sleep deprivation, mood swings, and       unpredictable hot flushes. Before menopause, most women have a monthly       hormonal rhythm. When the cycle becomes disrupted by erratic hormonal       fluctuations, a woman's sense of well-being can be disturbed. These       changes also tend to occur at a time when women are more likely to       experience other life changes, including divorce, widowhood, children       leaving home, concerns about aging parents, and other caregiving issues.       Self-image is another important variable, and women with poor self-images       have more flush-related distress [20].       In combination, these factors may each contribute to a reduced global QOL       as well as decreased work productivity and difficulties with personal and       social relationships.

A large number of studies       have documented the negative impact of menopause on QOL. Ledesert and       colleagues studied a cohort of 289 women aged 45 to 52 years who were no       longer menstruating and reported lower HRQOL on several measures of the       Nottingham Health Profile compared with values for menstruating women [21].       A population-based study evaluated the effects of various medical       conditions on work impairment in more than 16,500 individuals [22].       Menopause was one of the factors associated with significant work       limitations. The impact of VMS on HRQOL has also been studied by Bobula       and colleagues, who evaluated 1,655 healthy, nonhysterectomized,       postmenopausal women ranging in age from 40 to 65 years who were not       receiving HT [23]. Their results       indicated a significant correlation between moderate to severe hot flushes       and decreased QOL. Women with moderate to severe hot flushes had       significantly poorer scores than women with no hot flushes on four of the       eight 36-item Short Form Health Survey (SF-36) subscales (vitality, bodily       pain, social function, and role limitations-emotional), the mental       composite score, and the Women's Health Questionnaire (WHQ), with       pronounced differences for VMS, sleep problems, sexual behavior, and       somatic symptoms. Women with moderate to severe hot flushes also had       significantly poorer scores than women with mild hot flushes on two of the       eight SF-36 subscales (vitality and social function) and five of the nine       WHQ domains, including VMS, sleep problems, sexual behavior, somatic       symptoms, and depressed mood. Finally, women with mild hot flushes had       significantly worse scores than women with no hot flushes on two of the       eight SF-36 subscales (vitality and role limitations-emotional) and on the       WHQ for VMS, sleep problems, somatic symptoms, memory/concentration, and       menstrual symptoms.

Impact of VMS on sleep, mood, and cognitive       function


Despite the lack of agreement in the medical literature about the       relationship between VMS on sleep quality, mood variability, and cognitive       function, these symptoms are, in fact, primary complaints of menopausal       women to their healthcare practitioners; as such, they are addressed in       this review.


The causes of menopause-related sleep disturbances are       controversial. It has been suggested that problems with sleep may occur in       older women independently of menopause. For example, nocturia increases       with age and may disturb sleep [24].       Depression, stress, and other factors (e.g., restless leg and other periodic       limb movement syndromes) may also contribute to sleep disturbances in       these patients [25].

Sleep disturbances also       have been specifically related to hormonal changes that trigger hot       flushes or night sweats, independent of age. A National Sleep Foundation       poll of 1,000 women between the ages of 30 and 60 years found that 36% of       perimenopausal, postmenopausal, and oophorectomized women experienced hot       flushes during the night [26].       In this study, 44% of women who experienced VMS while sleeping were       perimenopausal versus 28% of women who were postmenopausal. The poll also       showed that menopausal and postmenopausal women slept less than       premenopausal women. According to the National Sleep Foundation, women       with night sweats experienced an average of three occurrences per week.       These events disrupted sleep and led to daytime irritability [26].

Menopause-related VMS also       may be associated with insomnia and disordered breathing at night. More       perimenopausal and postmenopausal women than menstruating women have       difficulty falling asleep, staying asleep, and achieving refreshing sleep [26].       Insomnia symptoms in women in the various stages of menopause include       difficulty falling asleep (29%) and early awakening with an inability to       fall back to sleep (21%). Respiratory abnormalities also may contribute to       sleep disturbances in menopausal women. Results from a study of 589 women       indicated that those in the menopausal transition were at a greater risk       for complaints of sleep apnea and hypopnea than were younger women [27].       Postmenopausal women had a 2.6-to 3.5-fold greater rate of       sleep-disordered breathing than their premenopausal counterparts [27].       Because sleep complaints are part of menopause-associated VMS, disordered       breathing is often overlooked as a potential cause of menopause-associated       sleep disturbance [27]. Although       these and other results have suggested a correlation between the       occurrence of hot flushes and sleep complaints in menopausal women, only a       few studies have employed objective methods for sleep evaluation (eg,       polysomnography, actigraphy, quantitative electroencephalographic       analysis). Results from these assessments have indicated that hot flushes       correlate with the occurrence of objectively demonstrable sleep disruption       in at least some women [28].

Inadequate and       unrefreshing sleep can have many consequences. Over time, disruption of       sleep secondary to hot flushes and/or night sweats leads to chronic sleep       deficits, significantly impaired alertness and mental acuity,       carelessness, forgetfulness, and decreased work productivity. In some       cases, night sweats can drench bedclothes and sheets, further disrupting       sleep and necessitating a change of clothes and covers, which can also       disturb the sleep of the individual's bed partner. Thus, lack of sleep,       tiredness, and irritability can affect daytime productivity as well as       familial and social relationships.


Menopause-associated changes in mood may result from a wide range       of variables, including elevated sensitivity to environmental events       secondary to decreased hormonal levels, changes in socioeconomic and/or       marital status, culture, lifestyle factors, level of education, and       history of depressive symptoms [29,30].       Longitudinal and cross-sectional studies carried out to date have not       indicated a consistent relationship between the menopausal transition and       increased risk of mood disorders [31,32].       However, results from the prospective population-based Melbourne Women's       Midlife Health Project, which followed 438 women for 11 years and used the       Center for Epidemiologic Studies Depression Scale to measure depression,       indicated that depression scores were highest for women who were in the       menopause transition stage (ie, had not reached their final menstrual       period) or who had experienced surgical menopause. Current use of HT was       associated with lower Center for Epidemiologic Studies Depression Scale       scores (ie, less severe depressive symptoms) in this cohort [33].       These epidemiologic results are consistent with those from a small-scale       clinical trial that demonstrated the significant benefit of short-term HT       in perimenopausal women with depression [34].       It is important to note that many studies investigating mood and VMS have       used depression scales. There are important distinctions between mood       variability and major depression. It is incorrect to interpret the results       from depression and simply extrapolate these findings to mood. Hopefully,       new studies will address this issue and develop specific scales to       delineate the impact of VMS on mood.


Memory impairment is directly related to hot flushes in women who       have undergone oophorectomy, but natural menopause itself does not       necessarily result in significant cognitive dysfunction [35].       During a hot flush, blood flow decreases in the hippocampus, possibly       impairing memory and cognition [35].       It has been suggested that such reductions in blood flow may contribute to       the decreased mental clarity and short-term verbal memory problems       experienced by many perimenopausal and postmenopausal women [35].       The importance of estrogen in cognition has been demonstrated by Jacobs       and colleagues, who measured cognitive function and verbal memory in 727       older women (average age, 74.2 years). Study results demonstrated that       cognitive test scores and verbal memory were superior in the women who       received HT compared with those who did not [36].

Costs associated with VMS and their treatment


In the year 2000, there were approximately 50 million women aged 45       to 60 years in the United States; as life expectancy increases, that       number will increase [1]. Many of       these women will use the health care system for premenopausal,       perimenopausal, and postmenopausal needs. These requirements pose a high       economic burden on the women themselves and on the health care system       (Figure 

Determining the       cost-effectiveness of treatments aimed at relieving VMS is complex.       Analysis must consider the direct costs of treatment, costs associated       with treatment-related adverse events, and the health care costs saved       with effective therapy [37,38].       Cost-utility analysis of treatment for VMS also considers the impact of       treatment on improvements in QOL associated with the alleviation of       symptoms. This impact of treatment is expressed in quality-adjusted life       years (QALYs) [39].

Since the publication of       results from the WHI in 2002, therapy for menopausal symptoms has       undergone a dramatic transition. A marked decline has been seen in       prescriptions for oral estrogen and HT. Prescriptions for oral estrogens       declined from 56.8 million in 2001 to 37.2 million in 2003. The respective       values for oral HT were 24.0 and 10.3 million [40].       However, the pendulum has swung from fear to a greater understanding of       the risks and benefits of HT [41].

Costs incurred for the       management of menopause-related VMS include visits to physicians;       follow-up visits and telephone calls for the management of       medication-related side effects and changes in medication; self-prescribed       over-the-counter remedies, including complementary alternative medications       (CAMs); HT; laboratory tests; lost productivity at work; personal costs       for hygiene-related supplies; energy costs for the increased use of air       conditioning; and extra laundry requirements for clothing and bed sheets       soiled with sweat. A recent Gallup poll of menopausal women showed that       hot flushes and night sweats were the first-and second-ranked symptoms       that prompted physician visits. Among the women surveyed, 70% complained       of hot flushes, 68% complained of night sweats, 50% had mood changes and       moodiness, and 49% experienced insomnia and sleeplessness [42].       The costs associated with many of these symptoms have not been quantified,       but they undoubtedly result in a significant burden for the women who       experience them.

Before seeking medical       advice at the onset of VMS, women are likely to obtain information from       their peers, family members, or the Internet. In many cases women resort       to self-diagnosis and treatment. They may combine over-the-counter drugs       with medications prescribed for other conditions (eg, analgesics for       headache; anxiolytics and antidepressants for anxiety, tension, and mood       changes; sedatives/hypnotics for insomnia). Most of these treatments fail       to provide significant relief of VMS, and many women ultimately consult       their physicians after these remedies fail. Physician visits for VMS       include an initial visit to a primary care physician and, potentially,       follow-up visits to a gynecologist or CAM specialist. Subsequent visits       and telephone calls are often needed for medication adjustment, laboratory       testing, and managing side effects. In addition, women may seek counseling       from a psychologist or psychiatrist for mood changes, insomnia, and       difficulties with family and social interactions. Women may also visit a       neurologist for relief from headaches and/or help with cognitive deficits.       All of these factors add to the economic burden of VMS.

Economic burden of therapy for symptom       resolution

The economic burden of VMS management remains high even with       the use of HT. Costs associated with HT include one or two visits for       diagnosis and medication prescription as well as follow-up visits and       telephone calls to manage side effects and evaluate the efficacy of       therapy. Serious, but rare, adverse events associated with HT can lead to       exceptionally high acute and chronic costs [43].       Evaluation and management of more common transient adverse events,       including vaginal and uterine bleeding, breast discomfort, and breast       nodularity, can also add significantly to the overall cost of HT for       menopause-related symptoms. Approximately one third of patients who use HT       switch to another form of therapy or make medication adjustments because       of adverse events or compliance problems, increasing the overall cost of       therapy [43].       

Despite the complexities       associated with determining the cost-effectiveness of HT for the treatment       of women with menopause, several pharmacoeconomic analyses support the use       of such treatment. Results from an early evaluation by Weinstein suggested       that HT was cost-effective in menopausal women with prior hysterectomy or       osteoporosis, but not in asymptomatic women with an intact uterus. The       evaluation included information about the risks of endometrial cancer,       uterine bleeding, and gallbladder disease as well as the benefits       associated with the relief of menopausal symptoms and prevention of       osteoporosis and fractures [44].

Although long-term       continuous-combined HT (0.625 mg/day of conjugated estrogens plus 2.5 mg       of medroxyprogesterone [CEE/MPA]) has been associated with the potential       for increased health risks in some women, therapy limited to ≤5       years is no doubt beneficial for decreasing VMS, somatic symptoms, and       resultant sleep and mood disturbances in women who experience bothersome       menopausal symptoms. Moreover, short-term, low-dose therapy may minimize       the risk of adverse effects associated with longer-term HT [45].       Botteman and colleagues compared the cost-effectiveness of short-term CEE/MPA       0.625/2.5 mg against that of norethindrone acetate 1 mg and ethinyl       estradiol 5 μg (NA/EE), another       continuous-combined HT with a different side-effect profile, and no       interventional therapy for the management of moderate to severe VMS [45].       Anticipated 1-year baseline costs for the management of VMS included drug       acquisition costs ($357 for NA/EE vs $474 for CEE/MPA), initiation of       therapy requiring two physician visits ($132), HT-related breakthrough       bleeding requiring endometrial biopsy and associated visits and laboratory       testing ($345), or spotting requiring a telephone call to the physician       ($16), and two physician visits for VMS plus clonidine therapy ($162;       Table 

) [45]. Results from this analysis       indicated that NA/EE was less expensive and more effective than CEE/MPA in       QALYs. The cost-effectiveness of NA/EE was greater for patients with       severe VMS than those with mild symptoms. NA/EE also was more       cost-effective than no treatment, unless the symptoms were so mild that       the discomfort of spotting or bleeding (the most common significant       adverse effects of short-term HT) offset the QOL improvements associated       with HT [45]. It also should be       noted that the health risks associated with shorter-term (1 to 5 years) HT       for the treatment of VMS are not known. Another trial evaluating NA/EE       against CEE/MPA 0.625/2.5 mg or no therapy in premenopausal and       perimenopausal women indicated that NA/EE is cost-effective as first-and       second-line therapy [46].       Results from this study showed that NA/EE increased costs and QALYs       compared with CEE/MPA and no therapy. Despite the increase in direct costs       over no therapy and CEE/MPA, the cost effectiveness of NA/EE compared to       no therapy is based on a decrease in the cost of treating menopausal       symptoms, vaginal bleeding, and hip fractures and assumes a substantial       increase in compliance compared to CEE/MPA as a result of improved control       of bleeding with NA/EE. Results from a study reported by Ohsfeldt et al.       indicated that the 1-year cost of HT for treating VMS was approximately       $300 greater than the cost associated with no treatment [47].       It is not clear how results from this Canadian analysis would apply to the       United States since health care is much less expensive in that country.

As noted, the published       results from the WHI have dramatically reduced the use of estrogen and HT       by menopausal women. Results from the WHI prompted reanalysis of the       cost-effectiveness of HT by investigators at the Stockholm School of       Economics. Generalization of results from this analysis may be limited       because Sweden has a national socialized medical system. However, the       authors suggest that HT remains a cost-effective therapeutic strategy for       women with menopausal VMS compared with no therapy [47].


Selective serotonin reuptake inhibitors (SSRIs) and       serotonin-norepinephrine reuptake inhibitors (SNRIs) have received       increased attention for the management of VMS in nondepressed menopausal       women [48]. As yet, there have       been no pharmacoeconomic analyses of any agents in these classes for this       indication. Results from a recent systematic review of published economic       evaluations of interventions for depression indicated that SSRIs and SNRIs       are more cost-effective than older antidepressant medications (eg,       tricyclic antidepressants) owing to their greater efficacy and decreased       side-effect profile [49].


Other prescription medications approved for use in conditions not       associated with menopause-related VMS have demonstrated varying degrees of       efficacy [48]. The economic       advantage for some of these medications is that they have been on the       market for a number of years. Given the understanding that the VMS are the       result of a dysfunction in thermoregulatory circuitry, new nonhormonal       therapies that selectively target the serotonin and norepinephrine       pathways, without the involvement of other pathways, seem likely to become       the next generation of care for the management of VMS.


Many symptomatic menopausal women are likely to treat themselves       before consulting a medical practitioner, thinking that       "natural" products are safer and the ingredients more pure than       synthetic agents. Cost analysis was carried out for CAM treatments that       women would commonly find through a basic search on the Internet using the       terms 

as search       parameters. The most common CAM treatments that emerged were products       containing individual and compounded formulas of herbs, isoflavones, and       dietary supplements that promised to alleviate menopause-related hot       flushes and night sweats, irritability, sleeplessness, mood swings, weight       gain, headaches, insomnia, depression, menstrual irregularities, fatigue,       and loss of sexual desire. These formulations also claim to promote mental       clarity, increase energy levels, and improve physical performance [50-53].       The initial cost of a single product ranged from $19.95 to $58.00 per       month (Table 

).       A key limitation in the analysis of these products is that their       clinical efficacy has generally not been documented by results from       controlled clinical trials. It has also been noted that any benefits       associated with herbal supplements may occur more slowly than those       achieved with traditional medications [54].       Comparison of 1-year costs of CAM treatments versus HT indicated that       three of seven alternative treatments were more expensive than traditional       therapy (Table 


       Menopause-related VMS are very common and can be associated       with a high patient and societal burden. These symptoms result in high       direct and indirect costs and significantly reduced QOL. Current       treatments for VMS include HT, prescription medications developed for       other indications, and CAM treatments. Short-term HT has been shown to be       cost-effective for the management of VMS, but the publicity given the WHI       has substantially decreased the use of these treatments. The physiology       underlying VMS is complex and not fully understood, but it is clear that       alterations in noradrenergic and serotonergic mechanisms during       hypothalamic thermoregulation are involved in their development. A       significant unmet need remains for menopause-related VMS treatment       options. Among women who are eligible for the treatment of       menopause-related VMS, 80% do not seek treatment, receive inadequate       counseling, or do not have access to local medical aid [39].       The development of therapies that specifically target VMS may provide high       efficacy and reduced risk of serious and potentially costly adverse       events, thus increasing the overall cost-effectiveness of therapy.       

CAM Complementary       alternative medication

CEE/MPA Conjugated       estrogens plus medroxyprogesterone acetate

HRQOL Health-related       quality of life

NA/EE Norethindrone       acetate plus ethinyl estradiol

SF-36 36-Item Short Form       Health Survey

SNRI       Serotonin-norepinephrine reuptake inhibitor

SSRI Selective serotonin       reuptake inhibitor

SWAN Study of Women's       Health Across the Nation

Many women experience vasomotor symptoms at or around the time of menopause. Hot flushes and night sweats are considered primary menopausal symptoms that may also be associated with sleep and mood disturbances, as well as decreased cognitive function.

Psychosocial and Socioeconomic Burden of Vasomotor Symptoms in Menopause: A Comprehensive Review

Sixteen years since its  inception, The North American Menopause Society has become the leading  organization focused on promoting the health and quality of life for women  through an understanding of menopause. The organization has experienced  phenomenal growth through the years, and present-day NAMS leaders look  to the future with confidence.

“As we look to the future, we must always remember the past,” says  Wulf H. Utian, MD, PhD, Executive Director and honorary Founding  President of NAMS. “It’s important to realize that it has been a long  journey to get to where we are today.”

Dr. Utian has devoted his life to the study of menopause and has  been instrumental in educating the consumer and scientific populations  on the subject. Generations ago the subject of menopause was surrounded  by misconceptions and myths and largely ignored, both by the healthcare  community and society. Women were on their own to deal with problems  linked to the loss of their ovaries and low levels of estrogen.

Today’s women may spend half their lives living beyond this natural  part of aging. The North American Menopause Society has helped women  worldwide face the second stage of life in a different light, one filled  with new discoveries, fresh challenges – and hope.

 Dr. Utian was born, raised and educated in South Africa and completed  his residency in 1966 at the University of Cape Town, one of the leading  teaching and research institutions in the country. At that time, he  had no interest in practicing medicine and planned to spend his career  in academia. During his search for a PhD thesis subject, a colleague  asked him to review a narrative paper on estrogen. It was during his  review of the medical literature that he became intrigued on the subject  of menopause. 

“In those days when anyone had surgery,  they remained in the hospital for ten, sometimes fourteen days,” say  Dr. Utian. “When women had hysterectomies, regardless of their ages,  their ovaries were removed because the belief was that they would become  infertile anyway and there was no point in leaving them in as they  might end up cancerous. Within 48-72 hours of surgery, I noticed younger  women began complaining of severe hot flashes and their doctors would  say ‘its part of the trauma of surgery, and you will get over it.’ Six  weeks later we’d see these same patients in postoperative clinic and  they were still complaining.”

Dr. Utian’s fascination with the subject of menopause continued and  he searched through medical literature for more information on the  subject. 

“There was literally nothing, no real research on menopause,” he  says. “I suspected the ovaries played a larger role than just being  organs related to fertility. They were producing hormones, and I  believed there must be something else going on.”

It was the late 60s and Dr. Utian began his thesis entitled, “The  Clinical and Metabolic Effects of Ovariectomy and the Role of  Replacement Exogenous Estrogens.” His goal was to find out what happens  clinically and metabolically to women of reproductive age when they are  given replacement hormones after their ovaries have been removed  surgically. He simultaneously began an endocrine fellowship in the  Department of Medicine at the University of Cape Town in South Africa  and published the first scientific papers and reviews on the subjects of  menopause and ovariectomy.

“As my research developed, I realized that I really wanted to  discover what the real symptoms and effects of the menopause were and  try to tease that out from the associated aging factors,” he says. “So  began my 40-year passion on the subject of menopause. I’ve been involved  in it ever since.”

Birth of the North American Menopause Society

In 1970, Dr. Utian traveled for the first time to the United States  to present a paper on menopause at the combined meeting of the American  College of Obstetricians and Gynecologists and the International  Federation of Gynecology and Obstetrics. At that time in the states,  there was little interest in the subject of menopause. His paper was the  only one presented on the subject of menopause and was scheduled during  the final session of the meeting. Only a handful of interested people  attended his session.

The following year Dr. Utian presented, once again, the only paper  on menopause at the annual meeting of the British Congress in Obstetrics  and Gynecology. While at the meeting, he met with Pieter van Keep, MD,  PhD, Director General of the International Health Foundation in Geneva.  Dr. Utian describes the day of their meeting as THE most historic day in  the history of menopause.

“Pieter was interested in menopause from the psychosocial aspect and  had done some research in Europe on the socio-economic impact of  menopause in five European countries,” says Utian. “I was only  interested in the science of the menopause, having just completed my PhD  on the clinical and metabolic effect of ovariectomy and the role of  exogenous replacement estrogens. It was the first science on the subject  and was incorporated into the first randomized trial on hormone therapy  ever done. We had a meeting of the minds and decided to create a club  and bring together researchers who were interested in the subject.”

Utian and van Keep shared a great passion on the subject of  menopause. They invited other researchers who shared their interest to a  series of meetings under the auspices of the International Health  Foundation in Geneva and published each meeting as a proceeding. In  1976, they held the first international meeting in France where 150  people attended from all over the world. At the next meeting in 1978,  the International Menopause Society was formed.

By the mid 1980’s Dr. Utian had traveled the world to at least  twenty countries, helping medical communities establish their own  national menopause societies. Between his travels and his work within  different societies, he had developed quite a network of colleagues in  every major city in the world. As interest in the subject of menopause  grew, experts in the field began to make important connections. One of  the pioneers in osteoporosis research, Chris Norden from the Mineral  Metabolism Research Institute in Leeds, attended a meeting with one of  his promising young investigators, Chris Gallagher, who would later  bring his knowledge and expertise to the United States.

“I was instrumental in starting menopause societies around the  world,” says Utian. “It became an embarrassment that there was not a  society in the Unites States. I put up announcements and asked if people  were interested in forming a society in the States, but got a really  poor response.”

After rumors began circulating about the creation of an American  menopause group, Dr Utian met with a colleague in New York to discuss an  upcoming New York Academy of Sciences meeting. During that trip, he  contacted a lawyer for legal advice about developing a not-for-profit  scientific menopause organization. The first step was to develop a board  of trustees, so Utian contacted people around the United States and  Canada who were involved in different aspects of menopause research. Dr.  Utian agreed to be a trustee as well.

The North American Menopause Society was founded in 1989, and later  that year about 300 people attended the first meeting of NAMS in New  York as a joint meeting of the Academy of Sciences and North American  Menopause Society. Historic ground was broken at the meeting as Utian’s  vision of a multi-disciplinary meeting came to fruition. The meeting  brought together professionals representing a variety of disciplines who  were intellectually interested in menopause, including clinical and  basic science experts from medicine, nursing, pharmacy, anthropology,  sociology, psychology and complementary/alternative medicine. The  results were phenomenal and the entire meeting was published as the full  annals of the New York Academy of Sciences.

In 1989, Dr Utian was named Chair In Reproductive Biology at Case  Western Reserve and the Director of Obstetrics and Gynecology at  University Hospitals of Cleveland. University Hospitals supported NAMS  for the next five years, and by the mid-90s, their offices became  flooded with letters from women all over the country with questions on  how to deal with menopause symptoms, how to find a doctor and how to  access healthcare. It became quite obvious that there was tremendous  consumer need, so Dr. Utian and his colleagues added a new facet to the  NAMS mission – it would become a reliable, trustworthy and  evidence-based source of information to the consumer. NAMS officially  became an outreach to consumers through the birth of the organization’s  URL at 

Today more than 6,000 women reach menopause each day in North  America alone, and the public health challenge has never been greater.  NAMS will continue to focus its considerable expertise to promote  scientific truth about menopause.

NAMS dedicates its efforts toward the activities, services and sponsorships that:

Stimulate, recommend, recognize and support research on  physiological, medical, genetic, psychological and culture aspects of  menopause and its translation into clinical practice;

Promote the exchange of multidisciplinary scientific knowledge of  menopause through efforts that include the annual scientific meeting and  the journal Menopause;

Delineate the scope of, and promote excellence in, menopause-related clinical practice;

Develop and distribute continuing professional education for healthcare providers, researchers and educators that increases understanding of menopause;

Enable women to participate actively in menopause-related  healthcare decisions by providing them with culturally sensitive,  scientifically accurate information;

Serve as the definitive, independent resource on menopause for healthcare professionals, researchers, the media and the general public.

The NAMS Annual Scientific Meeting remains the preeminent annual  meeting worldwide on menopause and the society’s journal, Menopause,  remains in the top three of the Science Citation Index (SCI) rankings.  Millions of NAMS printed materials have been received by consumers all  over the country and the website receives five million hits each month.  Both consumer and scientific education programs continue to be updated  and developed. The NAMS competency examination is recognized as the sign  of excellence for those who earn the credential.

The success of NAMS stems from the efforts of NAMS members, other  health professionals, the Central Office staff and the passion of a  young scientist who would not stop until his work was done. Throughout  his impressive career, Dr, Utian has juggled many positions – as  clinical practitioner, academic administrator, research center  administrator and executive director of NAMS. Many times, he says, he  came very close to relinquishing his responsibilities with the  organization, but has committed to stay involved through 2009, twenty  years after founding NAMS.

Dr. Utian says that the NAMS organization has taken a life of its  own and is devoting his final three years to raising money through  philanthropy to create menopause related medical education programs for  nursing schools and residency programs in medical schools.

“The NAMS organization has grown phenomenally,” he says, “and the  quality of the meeting has flourished and will continue growing. The  committees and people involved are extraordinary and we are at a huge  growth curve. I know when I give it up after twenty years; I will have  made a difference.”

Sixteen years since its inception, The North American Menopause Society has become the leading organization focused on promoting the health and quality of life for women through an understanding of menopause. The organization has experienced phenomenal growth through the years, and present-day NAMS leaders look to the future with confidence.

Author | Wulf H. Utian, MD, PhD, DSc

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