Early Menopause and Other Gynecologic Risk Indicators for Chronic Fatigue Syndrome in Women

J William M Tweedie

Well-Known Member
Abstract and Introduction


Objective. This study aims to examine whether gynecologic conditions are associated with chronic fatigue syndrome (CFS).
Methods. This study includes a subset of 157 women from a population-based case-control study in Georgia, United States, conducted in 2004-2009. Gynecologic history was collected using a self-administered questionnaire. Crude odds ratios (ORs) with 95% CIs and ORs adjusted for body mass index and other covariates, where relevant, were estimated for gynecologic conditions between 84 CFS cases and 73 healthy controls.
Results. Cases and controls were of similar age. Women with CFS reported significantly more gynecologic conditions and surgical operations than controls: menopause status (61.9% vs 37.0%; OR, 2.37; 95% CI, 1.21-4.66), earlier mean age at menopause onset (37.6 vs 48.6 y; adjusted OR, 1.22; 95% CI, 1.09-1.36), excessive menstrual bleeding (73.8% vs 42.5%; adjusted OR, 3.33; 95% CI, 1.66-6.70), bleeding between periods (48.8% vs 23.3%; adjusted OR, 3.31; 95% CI, 1.60-6.86), endometriosis (29.8% vs 12.3%; adjusted OR, 3.67; 95% CI, 1.53-8.84), use of noncontraceptive hormonal preparations (57.1% vs 26.0%; adjusted OR, 2.95; 95% CI, 1.36-6.38), nonmenstrual pelvic pain (26.2% vs 2.7%; adjusted OR, 11.98; 95% CI, 2.57-55.81), and gynecologic surgical operation (65.5% vs 31.5%; adjusted OR, 3.33; 95% CI, 1.66-6.67), especially hysterectomy (54.8% vs 19.2%; adjusted OR, 3.23; 95% CI, 1.46-7.17). Hysterectomy and oophorectomy occurred at a significantly younger mean age in the CFS group than in controls and occurred before CFS onset in 71% of women with records of date of surgical operation and date of CFS onset.
Conclusions. Menstrual abnormalities, endometriosis, pelvic pain, hysterectomy, and early/surgical menopause are all associated with CFS. Clinicians should be aware of the association between common gynecologic problems and CFS in women. Further work is warranted to determine whether these conditions contribute to the development and/or perpetuation of CFS in some women.

Chronic fatigue syndrome (CFS) is a debilitating and complex illness affecting more than 1 million US adults and accounting for sizable economic costs to the individual, healthcare system, and society as a whole.[1-5] CFS is characterized by profound fatigue that is accompanied by symptoms affecting multiple body systems, including, most characteristically, postexertional malaise, unrefreshing sleep, problems with memory and concentration, and pain.[1] The fatigue in CFS is not relieved by rest; medical or psychiatric conditions that could explain the fatigue and symptoms have been ruled out or fully managed.[1] The cause of CFS remains unknown. CFS affects women two to four times more frequently than men, with the highest prevalence found in women in their middle to late 40s.[3-6] Although CFS is more common in women, only few studies have examined sex-specific risk factors for CFS. A case-control study with a population-based sample of women with CFS (n = 22) identified hysterectomy as a risk factor for CFS.[7] Another case-control study of women with CFS (n = 150) from a tertiary referral center found endometriosis, ovarian cysts, polycystic ovaries, uterine fibroids, menstrual abnormalities, and galactorrhea to be risk factors for CFS.[8] Furthermore, Harlow et al [8] and Studd and Panay [9] hypothesized that a deficiency or imbalance in endogenous sex hormones may be a risk factor for CFS in some women. We recently reported that endometriosis, irregular periods, a history of gynecologic surgical operation, and pelvic pain unrelated to menstruation were all significantly associated with CFS in a population-based sample from Wichita, KS.[10] Using the conceptual framework that irregular periods, bleeding between periods, menopause, and oophorectomy could be indicators of gonadal hormone deficiency, we examined the association between gynecologic conditions and CFS in this study to replicate previous findings and to explore additional risk indicators.


Overall demographic characteristics of the CFS and control groups are presented in Table 1 . Women from the CFS and control groups did not differ significantly in age, race/ethnicity, or residential area ( Table 1 ). The CFS group was less educated, had a higher proportion of women who were previously married, and had a lower proportion of women who were never married. There was no significant difference in overall household income between the groups; however, a higher proportion of the CFS group belonged to the lowest-income category (<US$30,000) compared with controls (P = 0.047; data not shown in Table 1 ). The CFS group had significantly higher BMI than controls. Of the 55 women in the CFS group who had data on type of illness onset, most (76.4%) reported gradual onset of their fatigue (data statistics not shown in Table 1 ). Among women with CFS, the mean (SEM) duration of fatigue/ exhaustion was 10.1 (0.7) years.
Gynecologic Variables

Mean age at menarche was the same for CFS cases and controls (12 y; Table 2 ). The CFS group had a longer mean (SEM) duration of menstrual flow (5.7 [0.2] vs 4.8 [0.2] d for controls). A significantly higher proportion of women in the CFS group reported excessive bleeding during periods (73.8% vs 42.5% in controls), bleeding between periods (48.8% vs 23.3%), and missing periods (38.1% vs 21.9%), with OR ranging between 2.16 and 3.33 ( Table 2 ).
Significantly more women with CFS than controls reported having been diagnosed as having endometriosis (29.8% vs 12.3%; OR, 3.01; 95% CI, 1.30-6.98; Table 2 ). Pelvic or lower abdominal pain unrelated to menstrual period was significantly more common in women with CFS (26.2% vs 2.7% in controls; OR, 12.60; 95% CI, 2.85-55.73), and adjusting for endometriosis did not significantly alter this association ( Table 2 ).
Although women in the two groups were of similar mean age, a significantly higher proportion of women in the CFS group reported being menopausal (61.9% vs 37.0% in controls). In the subset of postmenopausal women (52 with CFS and 27 controls), those with CFS reported a significantly younger mean (SEM) age at menopause (38.5 [1.3] y) compared with controls (48.6 [0.9] y; Table 2 and Table 3 ). Hysterectomy was experienced by 78.8% (ie, 41 of 52) of postmenopausal women with CFS compared with 37% (ie, 10 of 27) of controls (P < 0.001; Table 3 ). Natural menopause occurred 2 years earlier in the CFS group compared with the control group (mean [SEM], 48.6 [1.7] vs 50.6 [0.5] y, P=0.25). Hysterectomy was experienced by women with CFS at a significantly younger mean (SEM) age (about a decade earlier) compared with controls (35.8 [1.2] vs 45.2 [1.8] y, respectively).
Major Gynecologic Surgical Operations

At least one gynecologic surgical operation was reported by 65.5% of women with CFS versus 31.5% of controls (OR, 4.12; 95% CI, 2.11-8.04; Table 2 ). Hysterectomy was the most common surgical operation (54.8% of women with CFS vs 19.2% of controls). As shown in Table 2 , most women who reported a hysterectomy also reported removal of ovaries and tubes. Stratified analysis by type of hysterectomy (alone, with bilateral oophorectomy, or with unilateral oophorectomy) is presented in Table 2 . CFS was significantly associated with any hysterectomy (OR, 5.10; 95% CI, 2.47-10.52), total hysterectomy alone OR, 5.12; 95% CI, 1.54-17.05), hysterectomy with bilateral oophorectomy (OR, 3.38; 95% CI, 1.25-9.16), or hysterectomy with unilateral oophorectomy (OR, 7.09; 95% CI, 1.44-34.88). Early surgical menopause (at or before age 45 y) occurred in 61.5% of postmenopausal women with CFS compared with 33.3% of postmenopausal controls (OR, 3.20; 95% CI, 1.21-8.49; P = 0.02; Table 3 ). Overall, mean age at time of surgical operation was younger in women with CFS than in controls, respectively: 35.8 (1.2) versus 45.2 (1.8) for any hysterectomy; 37.7 (2.7) vs 45.3 (2.5) for hysterectomy with bilateral oophorectomy; and 34.1 (1.4) vs 44.0 (3.6) for hysterectomy with ovarian preservation ( Table 2 and Table 3 ).
After adjustment for BMI, all gynecologic factors remained statistically significantly associated with CFS ( Table 2 ). There were no statistically significant interactions between gynecologic variables and BMI. When total hysterectomy, age at menopause, and BMI were included in the model, only age at menopause remained statistically significantly associated with CFS (OR,1.22; 95% CI, 1.09-1.36; P < 0.001; overall model fitting, 0.96; c = 0.84).
Conditions Leading to Surgical Operation (Reasons for Surgical Operation)

We compared the proportions of the most common reasons for removal of the uterus and ovaries in the two groups in two ways. First, in a stratified analysis, we broke down the variable "gynecologic surgical operation" ( Table 2 ) into several subgroups based on "reason for surgical operation." CFS was strongly associated with both bleeding (OR, 10.38; 95% CI, 2.33-94.22) and uterine fibroids (OR, 3.45; 95% CI, 1.01-15.01) as reason for gynecologic surgical operation (data not shown). Second, we used a conservative estimate by including in the denominator only women who reported gynecologic surgical operations ( Table 4 ). Bleeding (as reason for surgical operation) remained significantly associated with CFS (OR, 5.81; 95% CI, 1.01-59.12). Neither of the other examined reasons‐endometriosis, uterine fibroids, ovarian cysts, or precancerous cervical lesions‐differed significantly between cases and controls.
Relationship Between Time of Surgical Operation and CFS Onset

Of the 51 women who reported hysterectomy and/or bilateral oophorectomy and/or removal of both tubes, 42 had information on both date of surgical operation and date of onset of unusual fatigue. Of these 42 women, 30 (71.4%) had surgical operation before the onset of illness by a mean (SEM) of 9.1 (1.4) years (range, 0-21 y; median, 10.5 y). When we limited the analysis of hysterectomy to only 30 cases in which hysterectomy occurred before the onset of fatigue, the magnitude of the association of CFS with hysterectomy was reduced (OR, 1.56; 95% CI, 0.74-3.22; P=0.24).
Use of Noncontraceptive Hormone Therapy

Women with CFS were significantly more likely to have ever been prescribed hormonal preparations to treat irregular periods, menopausal symptoms, or bone loss: overall, 57.1% of the CFS group versus 26.0% of controls (OR, 3.79; 95% CI, 1.92-7.47), after adjustment for menopause status (OR, 2.95; 95% CI, 1.36-6.38). Interestingly, among the 14 women in the CFS group who were CFS cases at T 0 and classified in the ISF group at T 1, 35.7% reported currently using hormone therapy. Inversely, of the 12 women who were classified in the ISF group at T 0 and became CFS cases at T 1, only 16.7% (two women) were currently using hormones.


Our study supports previously identified associations of CFS with gynecologic conditions: endometriosis,[8,10,16] menstrual abnormalities,[8] gynecologic surgical operation (particularly hysterectomy),[7,10,17] and pelvic pain unrelated to menstruation.[10] In addition, our study found that CFS was associated with early hysterectomy/menopause and use of noncontraceptive hormonal preparations. The gynecologic conditions associated with CFS and the possible links between them are summarized in Figure 2. (Follow link to original article) As shown in Figure 2, we suspect that aberrations in female sex hormones may contribute to these associations; however, because of cross-sectional data, our findings do not demonstrate causality.


CFS in women is associated with self-reported menstrual abnormalities, endometriosis, pelvic pain unrelated to menstruation, early age at hysterectomy/surgical menopause, and other gynecologic conditions and surgical operations. It should be emphasized, however, that our findings do not demonstrate causality. These findings could be used for further hypothesis generation for future studies. Nevertheless, the significantly higher prevalence of various gynecologic conditions in women with CFS warrants clinicians' attention on tailoring these women's medical care. Gynecologists need to be aware that women who have had early hysterectomy and/or other gynecologic conditions discussed here may be at risk for CFS. Therefore, gynecologists need to assess these women periodically for symptoms suggestive of CFS (such as persisting/ relapsing problems with memory and concentration, sleep problems, muscle and joint pain without swelling or redness, persistent or relapsing fatigue that reduces previous levels of functioning, headaches of new onset or severity, postexertional malaise [ie, worsening of symptoms after mental or physical exertion], and other symptoms; for a detailed list of symptoms and differential diagnosis, see Fukuda et al [1]). When CFS is suspected, supportive care and appropriate clinical referrals are needed. Similarly, physicians seeing women with CFS need to carefully evaluate their gynecologic history for risk factors associated with CFS and work with gynecologists for further management of identified gynecologic problems. The exact reasons for the reported associations cannot be determined from this study; future studies need to examine whether any of the associations reported here may be pathophysiologically related to the onset or perpetuation of CFS in some women. Further work may be warranted to determine whether aberrations in endogenous sex hormones contribute to the pathogenesis and/or perpetuation of CFS in a subset of women with this illness.


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