SWAN: Key Findings to Date and more to Come

“SWAN is compiling the most comprehensive characterization to date of the health of women from premenopause to postmenopause in a community-based sample.”

The Study of Women's Health Across the Nation (SWAN) study is a multicenter, multiethnic longitudinal study designed to characterize a number of physiologic, psychosocial and behavioral changes that occur during the menopausal transition and to observe their effects on subsequent health and risk factors for age-related diseases. A total of 3302 women were enrolled at seven clinical sites in the latter half of the 1990s. At the time of enrollment, women were pre- or early peri-meno-pausal, not taking hormones, and between 42 and 52 years of age. They were followed annually for 10 years, and then every other year.

SWAN has a multidisciplinary focus and thus has repeated measures of bone health, cardiovascular risk factors, psychosocial factors and ovarian hormones.

SWAN is compiling the most comprehensive characterization to date of the health of women from premenopause to postmenopause in a community-based sample. It is now poised to study the effects of these menopause-related changes on subsequent patterns of healthy/unhealthy aging and on age-related diseases in the postreproductive period, focusing on outcomes such as fractures, depression, subclinical cardiovascular disease, cardiovascular events and physical and cognitive functioning.

Much of the knowledge about the timing of the final menstrual period (FMP) in healthy women has been affected by the nature of the samples of women studied and key methodological differences across studies (e.g., the age range included in the sample and inclusion or exclusion of women who have had a hysterectomy). However, the age at FMP may be a marker of overall somatic aging and health, and thus portend future health risks [1]. Smoking, lower parity and lower socioeconomic status have all been associated with earlier menopause [2], and early menopause is an indicator of reduced longevity [1].

The SWAN cohort includes women from five different ethnic backgrounds. Participants self-identified as non-Hispanic Caucasian (47%), African–American (28%), Japanese (9%), Hispanic (8%) or Chinese (8%). Race/ethnicity has been found to be a very important predictor of the menopause experience, both in terms of the timing of menopause, as well as the key symptoms that are perceived as most bothersome. Early/premature menopause was most common in Hispanic and African–American women and least common in Japanese–American women [3]. Hot flushes are consistently reported as most bothersome by African–American women and vaginal dryness was most prevalent among Hispanic women [4].

A consistent finding in SWAN has been that late perimenopause (≥3 months of amenorrhea) coincides most strongly with both symptoms and measurable physiologic changes across many health areas. Transition to late perimenopause is associated with the greatest odds ratio for vasomotor symptoms (adjusted odds ratio: 6.64) and risk for new onset of major depression (see below) [4]. Bone loss accelerates detectably in the late perimenopause, but not before, to an average loss of 0.018 g/cm² per year in the spine and 0.010 g/cm² per year in the hip [5]. Rates of bone loss are also influenced by body size, with greater bone loss among nonobese women and those with lower body mass, independent of race/ethnicity [5,6]. The greatest reduction in bone mineral density occurs in the year before the FMP and the first 2 years after the FMP, with lower rates of loss during the ensuing 1–7 years [6]. These data indicate that bone loss is a relatively late event in the menopausal transition. There is, therefore, no indication for estrogen treatment for osteoprotection prior to the onset of prolonged amenorrhea; however, symptomatic women who are taking estrogen for other reasons will avoid bone loss at this time of life. Postmenopausal estrogen therapy for the prevention of bone loss is currently a secondary option as there are a variety of nonhormonal antiresorptives that are considered preferable. It should also be remembered that, once the estrogen is discontinued, there is a rapid loss of bone that recapitulates the losses seen in the early postmenopausal period in SWAN [7,8].

Furthermore, significantly higher odds of depressive symptoms are reported by women who reach the late perimenopause. This finding was seen in women who began the study with a low Center for Epidemiologic Studies Depression Scale score, indicating that the depressive symptoms were of new onset and appeared to be directly related to the late perimenopausal transition [9]. Follow-up studies using a Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Axis I Disorders (SCID) confirmed that the late perimenopause is a vulnerable window for new onset major depression [10]. The late perimenopause may also be uniquely associated with alterations in hemostasis [11] and a higher prevalence of sleep difficulty [12].

The incidence rate for cardiovascular diseases, the leading cause of death in women, increases after the age of 50 years, when most women are transitioning to menopause [13]. This relationship has long been taken to mean that the loss of ovarian function is associated with cardiovascular disease. Late perimenopausal and postmenopausal women have larger common carotid artery luminal and adventitial diameters when compared with premenopausal and early perimenopausal women. This suggests that declining estrogen levels might be associated with vascular remodeling [14]. SWAN's longitudinal carotid ultrasound study has demonstrated for the first time that the progression rates of carotid intima–media thickness and common carotid adventitial diameter increase substantially at the late perimenopausal stage, irrespective of age at baseline and ethnicity [15]. These data strengthen the causative inference that estrogen loss leads to adverse changes in blood vessels – both luminal and extraluminal – and further implicates the late perimenopause as a stage of life during which arteries become more vulnerable [15].

Another interesting set of observations in SWAN has begun to shed light on the link between bodyweight and hormone levels. Higher BMI is associated with worse vasomotor symptoms as women traverse the menopause [16], owing perhaps to increased insulation of the body by fat or to increased inflammation related to adiposity, but this relationship seems to reverse once women become postmenopausal [17]. Obese postmenopausal women are believed to have fewer vasomotor symptoms because of peripheral conversion of circulating androgenic precursors to estrogens by adipose tissue, a process that preserves estrogen production after the ovaries cease to make estrogen. Women with a high BMI have lower gonadotropin and estradiol levels before menopause and have a lesser decline in estradiol associated with the transition [18], supporting a less steep trajectory of estrogen loss with menopause.

“Race/ethnicity has been found to be a very important predictor of the menopause experience…”

The SWAN study is continuing to follow women beyond the transition and through their postmenopausal years. The collection of a variety of health outcomes will allow us to determine the extent to which the menopausal process influences subsequent health and disease, and provide women and their healthcare providers with crucial information that will help them adopt lifestyles that are most conducive to healthy aging.

Disclaimer

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging, National Institute of Nursing Research, Office of Research on Women's Health or the NIH.