Discussion
Our study supports previously identified associations of CFS with gynecologic conditions: endometriosis, menstrual abnormalities, gynecologic surgical operation (particularly hysterectomy), and pelvic pain unrelated to menstruation. 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. 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.
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Figure 2.
Schema of possible links between various gynecologic conditions found to be associated with chronic fatigue syndrome (in this and other studies). This conceptual model warrants further investigation. Boxed text, findings from this study; underlined text and dotted black lines, findings/ hypothesis from other studies. *Reported by Studd and Panay; hypothesized by Harlow et al, by Boneva et al, and in the current study. PCOS, polycystic ovary syndrome.
In our study, women with CFS were four times more likely than controls to have had a hysterectomy. Most importantly, hysterectomy was performed at a significantly younger mean age in CFS cases than in controls. Our finding that only age at menopause remained significantly associated with CFS in the multivariate model (covariates: hysterectomy, BMI, and age at menopause) suggests that the risk for CFS increases with earlier reduction/depletion of endogenous sex hormones. Indeed, premenopausal hysterectomy (even with ovarian preservation) precipitates ovarian failure, with documented reduction of estrogen and progesterone levels and elevation of follicle-stimulating hormone (FSH) levels. The reported early menopause (mostly postsurgical) in the CFS group (mean, 38.5 y; ie, 10 y earlier than controls) bolsters our previous (not statistically significant) observation in a sample from a population-based case-control study in Wichita, KS. Before this study, a significant association of CFS and early menopause has not been reported. However, in fibromyalgia, which shares many symptoms with CFS, early menopause (<45 y) was reported by 38% of women in one study. In another study, 48% of women with fibromyalgia had a hysterectomy. Hysterectomy preceded fibromyalgia diagnosis in 90.7% of cases who had both conditions. Similarly, in our study, hysterectomy and oophorectomy preceded fatigue onset in 71% of women with available data on both. Although associations between hysterectomy and severity of illness have not been studied in women with CFS, in fibromyalgia, women who have had hysterectomy have lower physical function and greater severity of pain, fatigue, stiffness, and depression than those who have not had hysterectomy. In our study, CFS was also associated with menstrual irregularities and excessive bleeding conditions, which often may have hormonal reasons. Disturbed menstrual cycle function (including hyperprolactinemia and hyperandrogenism) in women with CFS has been suggested by Harlow et al but has barely been explored. A small study reported sex hormone deficiency in women with CFS and improvement in 80% with use of cyclic estrogen/progestogen. Reduced levels of ovarian sex hormones in early hysterectomy/ early ovarian failure can have considerable nonreproductive consequences because sex hormones are involved in a variety of nonreproductive bodily functions (see later discussion). The significantly higher use of noncontraceptive female hormones in our CFS group may be explained by earlier menopause and/or other sex hormone abnormalities requiring additional hormonal support. Although the numbers were quite small to draw any conclusions, the proportion of current hormone use was twice as high (35.7%) in the subgroup that converted from CFS to ISF (ie, improved) between T0 and T1 compared with the subgroup that converted from ISF to CFS (current hormone use, 16.7%).
Of the gynecologic conditions examined in this study, the strongest association was found between CFS and pelvic pain unrelated to menstruation (with pelvic pain being least reported by controls [2.7%]). Possible increased pain sensitivity may underlie this association. Increased pain sensitivity may exist in several overlapping pain conditions (CFS, fibromyalgia, endometriosis, irritable bowel syndrome, and interstitial cystitis), with women often having more than one condition. Both estrogen and progesterone modulate pain in the nociceptive pathways in the spinal cord and at the central level (via interaction with the serotonin system). Similar to our findings, women with interstitial cystitis/painful bladder syndrome have reported higher use of noncontraceptive female hormones, suggesting coexisting hormonal problems. Both estrogen and progesterone have numerous nonreproductive functions : they are neuroprotective ; they influence sleep, cognition, and immune responses/inflammation ; they support muscle, joint, and bone health ; and they modulate pain sensitivity —all of which are present in the symptom domains of CFS. A detailed discussion of the various nongynecologic effects of female hormones is beyond the purpose of this study. Notably, however, both physical and mental stressors, which have been implicated in the pathogenesis of CFS, can compromise sex hormone production via the hypothalamopituitary axis.
Although our sample size (N = 157) was not large, the study's strengths include its population-based design (with sample identified from random-digit-dialing telephone screening interviews covering 19,807 residents in Georgia), detailed gynecologic history, and extensive clinical workup to correctly define cases and controls and to rule out conditions other than CFS that could explain the symptoms. Limitations of our study include self-reported (not chart-abstracted) conditions, potential selection bias (from nonparticipation), inability to adjust for tobacco and alcohol use, and possible recall bias. However, completing the questionnaire at home allowed participants to consult their medical records, which potentially reduced recall bias. Furthermore, validation studies of self-reported hysterectomy and bilateral oophorectomy have shown high PPVs (97% and 100%, respectively) with moderate specificity (ie, underreporting of bilateral oophorectomy). Our study sample was population-based and was identified using the 1994 case definition; therefore, it may not be representative of women with CFS seen in tertiary clinical practice. The findings may also not be generalizable to all women with CFS because most cases in our study had gradual CFS onset. In our study, some women who have had hysterectomy (alone or with unilateral oophorectomy) were possibly misclassified as menopausal if their hysterectomy occurred before biological menopause. Therefore, in women who have had hysterectomy with ovarian preservation, age at menopause was probably an underestimate. However, even if we disregard age at menopause for the abovementioned reason and examine only mean age at hysterectomy as a risk factor, the CFS group had a significantly younger age at hysterectomy (mean, 8-10 y earlier than the control group; Table 2 ), and early hysterectomy (at <45 y) was significantly more common in the CFS group. Although ovarian function will probably continue after removal of the uterus with ovarian preservation (ie, hysterectomy alone or with unilateral oophorectomy), prospective cohort studies with FSH measurement show that ovarian function declines more rapidly and that menopause occurs earlier compared with same-age women who have not had hysterectomy. For example, premenopausal women who have had hysterectomy with ovarian preservation reach menopause (confirmed by FSH levels >40 IU), on average, 3.7 years earlier than similar-age women who have not had hysterectomy. Furthermore, among women who have had hysterectomy, those who have had unilateral oophorectomy reached menopause 4.4 years earlier than women with both ovaries preserved.