Although hsCRP levels in women with AN are lower than in healthy women, more than 20% of women with AN on OCPs fell into the high-risk (hsCRP > 3 mg/liter) category, despite profound undernutrition. Women with AN who were receiving OCPs had a higher mean level of hsCRP than women with AN or HC not receiving oral estrogens/progestins. A relationship was clearly seen between IGF-I and hsCRP levels in healthy women, although this relationship was not observed in AN, likely due to underlying suppression of IGF-I in these women by undernutrition.
In a survey of Society for Adolescent Medicine physicians by Robinson et al.
), 78% of respondents said they prescribed hormone replacement therapy to their patients with AN. Although bone loss is a major complication of AN (24
), prospective trials have failed to show efficacy of OCP therapy alone in preventing or treating AN-induced bone loss in adults or adolescents (33
). Therefore, unlike other hypoestrogenemic states associated with bone loss, such as menopause or possibly functional normal-weight hypothalamic amenorrhea, there is no known therapeutic role for estrogen in AN. Contraception remains an indication for oral contraceptive use in this population. However, Robinson et al.
) found that fewer than 10% of prescribers were influenced by whether or not the patient was sexually active. Despite the lack of clear benefit for the majority of patients with AN receiving OCPs, they continue to be widely prescribed for this population. Therefore, determination of the risks vs.
benefits of OCP use in AN is important.
Whether OCP use in healthy young women is associated with increased CV risk is controversial. However, a recent meta-analysis of 14 studies showed that current use of low-dose OCPs increased the risk for myocardial infarction by 84% (37
). More data are available regarding CV risk associated with estrogen/progestin use in older women. The Heart and Estrogen/Progestin Replacement Study showed an early increase in events and no benefit overall in women with known CV disease, and the Women’s Health Initiative (WHI) trial demonstrated an increase in CV events in healthy women (38
). One proposed mechanism for this effect is an increased production of inflammatory cytokines, because elevated hsCRP is a consistent finding in women taking oral estrogens with or without progestins (10
In both diseased and apparently healthy populations, hsCRP is a hepatic marker of systemic inflammation and indicator of CV risk (42
). The Women’s Health Study prospectively evaluated more than 20,000 healthy postmenopausal women and found that of 12 lipid or inflammatory indicators, baseline levels of hsCRP provided the strongest predictor of subsequent CV disease (44
). Follow-up analysis after a mean of 8 yr confirmed that hsCRP exceeds LDL in predictive value (45
). It is important to note that because the mean age of participants in the WHI was 63 yr old, the generalizability of these findings to other groups of women, particularly younger women, remains to be determined. A meta-analysis including 14 studies and more than 2500 subjects estimated that those with baseline hsCRP levels in the highest third of the distribution had twice the risk of CV events than those in the lowest (46
). In the Physicians’ Health Study, hsCRP levels predicted sudden cardiac death in healthy men and suggested that chronic cardiac exposure to inflammatory mediators like hsCRP may directly promote arrhythmias (47
). The finding of an elevation of hsCRP in AN, a disease associated with structural cardiac abnormalities, electrocardiogram changes, and metabolic alterations and sometimes treated with medications that may predispose to rhythm disturbances, may be of potential concern over a period of prolonged exposure. Because the rate of CV events is low in young women, elevated hsCRP in women with AN receiving oral contraceptives predicts a small absolute increase in CV events in those women in whom AN is limited to a short period of time in their 20s. This is consistent with the preponderance of published data demonstrating elevated mortality rates for young women with AN attributable to suicide, complications of alcohol use, and arrhythmias (8
). A large proportion of deaths reported in this population are from undetermined etiologies, and an elevated incidence of CV events as a cause of death has not been demonstrated. The standardized mortality rate has been shown to increase with age for women with AN, although the specific cause or causes for this trend have not been identified (52
). For the growing number of women for whom AN is chronic and especially for those in whom it persists into menopause, our findings are therefore potentially significant.
Although oral contraceptive use and hormone replacement therapy clearly increase hsCRP, the mechanism is not understood, nor is it known whether the elevation in hsCRP is due to the progestin or estrogen component. However, the clinical significance of elevated hsCRP in this setting is strongly supported by the WHI prospective observational study, which showed that healthy women with comparable hsCRP levels had a similar risk of future CV events, regardless of whether they were receiving estrogens/progestins (53
). This suggests that elevated hsCRP is a strong predictor of CV events in women receiving estrogens/progestins as well as in those who are not. Of note, although none of the seminal hsCRP studies included women younger than 45 yr old, they all clearly demonstrated that the predictive value of hsCRP remained significant after controlling for age (44
), raising the possibility that elevated hsCRP levels in young women, particularly if sustained chronically, could be predictive of cardiac events later in life. The possibility that progestins, not estrogens, could be the cause of hsCRP elevations was also raised by the WHI, which reported that combined estrogens/progestins led to increased CV risk, whereas estrogen alone did not (38
). These data are consistent with a recent analysis from the randomized Post-menopausal Estrogen Progestin Intervention study that found that IL-6, a critical cytokine stimulus of hsCRP production, increased concurrently with hsCRP in women receiving estrogen plus progestins but was inverse to the rise in hsCRP in those receiving estrogen only (56
). The authors concluded that although progestins may promote hsCRP via an inflammatory pathway, estrogen likely stimulates hsCRP production independently and thus may not carry the same risk. This is consistent with a number of other studies examining estrogen effects on hsCRP, which have not reported a corresponding rise in IL-6 (41
). In addition, data in postmenopausal women demonstrated that transdermal and intranasal hormone replacement therapy preparations that avoid first-pass liver metabolism do not affect hsCRP levels, whereas oral estrogens consistently promote a rise in hsCRP (57
). This has led some to suggest that oral estrogens may directly stimulate hepatic hsCRP production independent of IL-6 or even of inflammatory pathways (38
). However, we found IL-6 levels to be elevated in women with AN receiving oral contraceptives who had elevated hsCRP levels. This suggests that in women with AN receiving oral contraceptives, elevated hsCRP may reflect systemic inflammation. Whether the etiology of the IL-6 elevation is the estrogen or progestin component of the OCP, or both, could not be determined by our study. Our data raise the very real possibility that elevated hsCRP in young women with AN could be predictive of future CV events, particularly if the hsCRP elevation is sustained chronically. Additional studies in this area are therefore merited.
The GH axis has been identified as a potential mediator of hsCRP production and may be a mechanism underlying the effect of OCPs to increase hsCRP in healthy women (4
). In addition to increasing hsCRP levels, oral but not transdermal estrogens suppress IGF-I production, likely reflecting a first-pass hepatic effect (61
). A randomized controlled trial of GH administration on CV risk markers in 40 men with GH deficiency demonstrated a decrease in hsCRP and IL-6 with GH treatment compared with placebo (4
). We have also shown that by normalization of IGF-I in acromegalic patients using a GH receptor antagonist, mean hsCRP increased from below normal to a level comparable to baseline healthy controls, independent of IL-6 levels (5
). The GH receptor antagonist reduces IGF-I and elevates GH levels. This suggests that IGF-I, rather than GH itself, is the mediator of effects on hsCRP. In our study, the expected drop in IGF-I with OCPs was not seen in women with AN, perhaps because of already suppressed IGF-I in the setting of starvation-induced GH resistance. We also found that although IGF-I was inversely associated with hsCRP levels in healthy women, this IGF-I to hsCRP relationship was not evident in AN, suggesting that a significant effect of OCPs on hsCRP is independent of the GH axis in AN.
This study is the first to report increased hsCRP in women with AN taking OCPs and lower hsCRP levels in those women with AN who are not receiving OCPs. Although, as anticipated, IGF-I levels were lower in healthy women receiving OCPs than those who were not, there was no difference in mean IGF-I levels between the AN groups, perhaps because of GH resistance. The inverse relationship between IGF-I and hsCRP observed in healthy young women in our study was not found in AN, suggesting that the OCP-induced elevation in hsCRP is not mediated by the GH axis. Lipoprotein levels in both groups of women with AN were well within the normal range likely due to low weight, the effect of OCP use on these levels were modest, and few patients had high-risk levels. In contrast, the elevation of hsCRP in women with AN receiving OCPs was substantial and resulted in a significant proportion of women with hsCRP above 3.0, a level associated with twice the risk of a future CV event compared with women with hsCRP levels in the lowest tertile (30
). IL-6 levels were elevated in women with AN receiving OCPs with elevated hsCRPs, suggesting that the elevated hsCRPs in this population reflect increased systemic inflammation. Additional research will be important to determine whether elevated hsCRP associated with OCP use in AN results in increased risk of CV events. Because no beneficial effect of oral contraceptives on bone density or other endpoints has been demonstrated, and our data demonstrate possible deleterious effects on CV risk, women with AN who are not sexually active should not be offered oral contraceptive treatment. In addition, alternatives to oral contraceptives, such as barrier methods, should be discussed with those who are at risk of becoming pregnant. However, because the consequences of pregnancy during AN can be serious, oral contraceptives should not be withheld from women with AN who are sexually active and unlikely to use alternative birth control methods, pending additional research in this area.