Results
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 T0 and classified in the ISF group at T1, 35.7% reported currently using hormone therapy. Inversely, of the 12 women who were classified in the ISF group at T0 and became CFS cases at T1, only 16.7% (two women) were currently using hormones.