Symptom experience during the late reproductive stage

Discussion

Although some women reach menopause easily, others experience a variety of unpleasant or even disruptive symptoms in the preceding years. Characterizing when these symptoms begin is important for providing anticipatory guidance to women, validating their lived experiences, and educating the healthcare providers who care for them: our goal is to contribute to this effort.

A total of 2,406 women responded to the WLB Survey, 1,436 of whom met criteria for the LRS or MT+ stages and rated 61 symptoms with respect to occurrence, frequency, and bother over the previous 3 months. A majority of this well-educated sample was employed for pay, did not have difficulty paying for basics, and described themselves as White. Despite 89% of participants rating their health as good, very good, or excellent, a majority indicated they experienced ‘‘not feeling like themselves’’ in the past 3 months.

The symptom experience of the LRS group is strikingly similar to the MT+ group for most symptoms. For only 8 of 61 symptoms did the LRS and MT+ groups differ by 10% or more in percentage reporting (Fig. 2). Of mean bother ratings, only hot flashes differed significantly between LRS and MT+ (Fig. 3). Overall, the LRS and MT+ groups were more similar than different with respect to symptom ratings across all four metrics — percentage reporting, frequency, bother, and burden.

WLB survey data indicate that women experience considerable symptomatology during the LRS before menstrual irregularity of a week or more, the STRAW criterion delineating the beginning of the MT. Women were asked to report only symptoms that were new or more common than in the past (ie, symptoms that had begun since their mid-30s). Indeed, when we examined the proportion of LRS women in our sample reporting symptoms, we found that more than 40% indicated awakening in the middle of the night and remaining awake for more than an hour, having night or cold sweats, feeling irritable, anxious, easily overwhelmed, being more forgetful, having difficulty concentrating, breast soreness, being less interested in sexual activity, experiencing urinary leakage when coughing or sneezing, dry skin, new facial hair, and fatigue.

Previous research has documented symptoms thought to be associated with menopause during the LRS. The aforementioned scoping review of the LRS found nine studies that identified symptoms including vasomotor, sleep, mood, cognitive, pain, and bladder symptoms.³

Vasomotor symptoms, a hallmark of the MT, have been commonly reported in studies of midlife women. In WLB participants 29% of the LRS group and 57% of the MT+ reported hot flashes and 40% and 51%, respectively reported night/cold sweats. This is similar to the proportion of POAS participants who reported hot flushes (35%) in the premenopausal stage which approximated the LRS. These increased as women entered PM.^22,23 SMWHS participants also reported hot flashes during the LRS that increased in severity from the LRS to the MT stages and PM.²⁴

Forgetfulness and difficulty concentrating were rated among the most burdensome and most frequently reported symptoms by WLB participants in both the LRS and MT+ groups. Rochester Investigation of Cognition Across Menopause participants in the LRS performed worse than women in the late MT stage on attention/working memory tasks, but better than women in PM on tests of verbal learning, verbal memory, and motor functioning.⁷ SMWHS participants reported memory problems (Memory Functioning questionnaire), including forgetfulness, that occurred more frequently during LRS and early MT than the late MT stage.²⁵ Similarly, POAS participants reported difficulty concentrating during the premenopause (analogous to LRS) at a similar rate as women in the early MT.²⁶

As in previous studies, fatigue was commonly reported and the most burdensome symptom in both LRS and MT+ groups in the WLB study. Joint and muscle pain and joint and muscle stiffness were among the most burdensome symptom for both LRS and MT+ women and the proportion reporting both was greater among the MT+ group. SMWHS participants also reported a variety of pain symptoms: back pain increased in severity from the LRS to the MT stages and PM, although joint pain did not change significantly across the MT stages.²⁷ In the POAS cohort, aches were the most prevalent symptom in the premenopause with increases through the late transition stage.²³

Sleep disruption has been documented in several studies of midlife women. Approximately 40% of POAS participants in the premenopause reported poor sleep.^23,28 Among SMWHS participants only severity of awakening during the middle of the night became more severe with progression through the MT stages.²⁹ The most frequently reported sleep disruption symptom by WLB participants in the LRS was waking in the middle of the night and being awake for more than an hour (42%). While each of the sleep symptoms was more common among the MT+ than the LRS group, none of the differences was statistically significant.

Irritability, anxiety, and feeling overwhelmed were the most reported mood symptoms by WLB participants in the LRS group. The percentage reporting anxiety and feeling overwhelmed was greater for the MT+ versus the LRS group, whereas the percentage reporting irritability was greater for the LRS group. Anxiety, irritability, and mood swings were commonly reported by LRS women in the POAS cohort, but a similar proportion of participants reported these mood symptoms across the MT stages.²⁷ Women in the West Pomerania Study also reported anxiety and mood disorders during the LRS.⁸ A significantly higher proportion of WLB participants in the MT+ group reported low feelings compared to the LRS group. Depressed mood symptoms were seen in 50% of women in the premenopausal stage and increased to 60% in the late premenopausal stage for POAS participants.³⁰ Similarly, SMWHS participants reported depressed mood symptoms during the LRS which became more severe during the MT stages.^31,32

More than 40% of LRS and almost 50% of MT+ women reported urinary leakage with sneezing or coughing. Leakage without sneezing or coughing was the second most bothersome symptom reported by both LRS and MT+ women, and it was the fifth most burdensome symptom for both groups as well. Symptoms of urinary incontinence and nocturia were more commonly reported by women in the LRS than in the MT stages in the University of California, San Francisco Women’s Health study.⁵ Participants in the SMWHS experienced urinary leakage related to coughing or sneezing more frequently during the early MT stage than during the later MT stage and PM.³³

There have been several longitudinal studies (eg, POAS, SMWHS, SWAN, Melbourne Women’s Midlife Health Project) contributing to understanding symptoms across the MT stages. Only POAS and SMWHS can, however, be used to evaluate the LRS stage as the others did not incorporate the STRAW framework. These studies corroborate that women experience some of the same symptoms during the premenopause (variously defined) as they do during the MT.

Our scoping review³ revealed that much research on late reproductive age women focuses on fertility, including the age-related loss of reproductive potential and success of in vitro fertilization (IVF) in older women. From this body of research, physiologic changes such as diminishing anti-mullerian hormone (AMH), decreased antral follicle count, and rising follicle-stimulating hormone (FSH), as well as considerable individual variation, have been identified in women with regular menstrual cycles,^34,35 but investigators have not yet correlated these to symptoms for women during the LRS.

One limitation of our work is that we were not able to collect hormonal data to align with staging or symptoms. Nonetheless, the information available to most clinicians as they encounter women with LRS-related complaints, age, and a menstrual history was included in our survey. We hope that data documenting symptoms often associated with the MT before menstrual cycle irregularity will empower clinicians to validate women’s LRS experiences.

Other limitations of this study include the use of an online survey, which restricted participation to those with access to technology. However, the online survey afforded women the ability to respond to questions privately, promoting honest responses. Also, our convenience sample clearly does not represent the general population of midlife women. Our sample is likely biased toward symptomatic women who would be motivated to complete the survey. In addition, the design was cross-sectional, precluding the ability to observe participants’ experiences over time. Finally, the survey was active during the first months of the COVID pandemic during which evidence suggests increased levels of anxiety were widespread.³⁶ Nonetheless, the WLB survey engaged a robust cohort of women who hoped to contribute to an improved understanding of symptoms during the LRS and educate the healthcare providers caring for them.

Another consideration is the effect of age on symptom experiences. Because the stages of reproductive aging occur in the context of general aging, we would expect some symptoms to be correlated with age and others with both age and stages of reproductive aging. We examined the relationship of age to all symptoms, estimating correlations between age and symptoms and partial correlations between stage (LRS and MT+) and each symptom, controlling for age. Burden associated with hot flashes, dryness and itchiness of skin, joint/muscle stiffness, pain with vaginal intercourse and decreased vaginal lubrication, and vaginal dryness were each positively associated with age (P < 0.001) (see Table, Supplemental Digital Content 2, which lists correlations of age and stage controlling for age with symptom burden (Pearson r and partial correlation). Breast soreness and cramps were both negatively associated with age (all P < 0.001). When controlling for age, partial correlations between stage and symptoms were significant for hot flashes, breast soreness, joint/muscle stiffness, pain with vaginal intercourse, decreased lubrication, and vaginal dryness (all P < 0.001).

The LRS and MT+ groups reported similar symptoms in type, frequency, bother and burden, and similar levels of symptom-related interference with relationships and daily living, while they did not anticipate these symptoms would occur until they were older. When these symptoms arise earlier than expected, women are surprised and concerned. In the absence of a 7-day difference between consecutive cycle lengths, healthcare providers may not view these symptom experiences as potentially related to the MT, particularly when women are in their late 30s and early 40s.

Our findings as well as those from previous research suggest that the LRS should be examined in greater detail in future studies. Moreover, clinicians should be alerted to the likelihood that symptoms on the path to menopause may occur during this earlier period of reproductive aging, whereas women’s cycles are still regular or when they are noticing only subtle changes to cycle length, days of flow, or amount of flow.