Richard A Van Konynenburg, Ph.D.
(Independent Researcher and Consultant)
8th International IACFS Conference on Chronic Fatigue Syndrome, Fibromyalgia and other Related Illnesses Ft. Lauderdale, Florida, U.S.A.
January 10-14, 2007
Epidemiological studies have found that the prevalence of CFS is significantly higher in women than in men.
Jason et al. (1) found a ratio of 1.8 (women to men) in a community-based study in Chicago, IL, USA, that included over 28,000 adults.
Reyes et al. (2) found a ratio of 4.5 (women to men) in a study in Wichita, KN, USA, that included nearly 24,000 households. Other studies in San Francisco, CA, USA (3), the U.K. (4), Australia (5), Sweden (6), Iceland (7) and the Netherlands (8) have also found significantly higher prevalence of CFS or CFS-like illness in women.
Children have been found to have a lower rate of incidence of CFS than adults, and there does not appear to be an effect of gender on the incidence of CFS in childhood:
- Carter and Marshall (1995) (9)
- Jordan et al. (2000) (10)
- Chalder et al. (2003) (11)
- Means et al. (2004) (12)
- Jones et al. (2004) (13)
- Farmer et al. (2004) (14)
- ter Wolbeek et al. (2006) (15)
This suggests that the transition to a higher relative rate of incidence of CFS in females occurs during adolescence, and thus that it may be related to increases in production of the female sex hormones, which occur at that time.
Hypothesis
1. Many people with CFS have polymorphisms in the genes that code for the detox enzymes that metabolize the estrogens, and in particular the dominant estrogen, estradiol.
2. These polymorphisms can be expected to occur equally in males and females, since these genes are autosomal (i.e. they are located on non-sex chromosomes). However, these polymorphisms would be particularly important in women who are in their potentially reproductive years, because of the higher production of estradiol in these women.
3. One result of the presence of these polymorphisms would be to increase the levels of semiquinones and quinones (16).
4. Semiquinones and quinones react back and forth between each other in a process that generates superoxide ions and is called redox cycling (17).
5. This redox cycling would produce an additional contribution to oxidative stress in these women that does not occur in men. Men’s bodies produce much lower amounts of estradiol (by the action of aromatase on testosterone), and the metabolism of the remainder of the testosterone occurs by different pathways that do not involve redox cycling (18).
6. According to the Glutathione Depletion—Methylation Cycle Block Hypothesis for the pathogenesis of CFS (19), oxidative stress depletes glutathione, which leads to the onset of CFS.
7. Therefore, women in their potentially reproductive years who have the relevant polymorphisms would have an additional factor biasing them toward onset of CFS that men do not have, and this would produce a higher prevalence of CFS in women than in men.
(Note that this redox cycling mechanism is well established and has been under study for several years because of its possible involvement in carcinogenesis (16, 17).
Rates of production of estradiol in males and females
Prepubertal children (20, 21)
- BOYS: 0.04 micrograms per day
- GIRLS: 0.3 micrograms per day
Men
- 50 micrograms per day (22)
Women (by menstrual cycle stage) (22)
- Early follicular 36 micrograms per day
- Preovulatory 380 micrograms per day
- Midluteal 250 micrograms per day
Normal Metabolism of Estradiol by Detox Enzymes (23,24)
The metabolism of estradiol (and of the estrogens in general) is complex, including a large number of alternative pathways and metabolites.
Most of the metabolism of estradiol occurs in the liver, while smaller amounts occur in other organs, including breast, uterus, brain, kidneys and ovaries.
Some estradiol is converted to estrone, and some is acted upon by various CYP450 enzymes to form multiple hydroxylated metabolites. Estradiol itself, estrone and these hydroxylated metabolites can be conjugated by other detox enzymes to form sulfates, glucuronides, or fatty acid esters. The various sulfate and glucuronide conjugates are the main metabolites that are excreted in urine and stools. Only the major pathways of estradiol metabolism are discussed in detail in the following.
The main hydroxylation reactions in the liver involve the CYP450 enzymes CYP3A and CYP1A2, and their chief product is 2-hydroxyestradiol, which is a catechol estradiol.
A smaller fraction of the total estradiol is metabolized by the enzyme CYP1B1, located in organs other than the liver. This reaction primarily produces 4-hydroxyestradiol, another catechol estradiol.
Most of the catechol estradiols are O-methylated by the enzyme catechol-O-methyltransferase (COMT) to form 2- and 4-methoxyestradiols, which are excreted.
Some of the catechol estradiol molecules escape the COMT reaction and instead are further oxidized by CYP1B1 to form semiquinones, which in turn are oxidized to form quinones. Normally, these are conjugated to glutathione by the glutathione transferase (GST) superfamily of enzymes and are excreted.
What would happen to estradiol metabolism if there were polymorphisms in the detox enzymes?
- CYP3A4 AND CYP1A2: Known polymorphisms that lower the activity of these enzymes would decrease the fraction of estradiol that is metabolized by them in the liver. This would have the effect of increasing the fraction of estradiol that is metabolized in other organs by CYP1B1.
- CYP1B1: Known polymorphisms that raise its activity would cause a greater rate of production of 4-hydroxyestradiol, and would also cause more of this to be oxidized to form semiquinones and quinones (16).
- COMT: Known polymorphisms that lower its activity would decrease the fraction of 4-hydroxyestradiol that is methylated, leaving more to be oxidized to semiquinones and quinones.
- GST enzymes: Known polymorphisms that lower the activity of members of this superfamily of enzymes would decrease the rate of removal of semiquinones and quinones, leaving more of them to carry on redox cycling and to contribute to oxidative stress (25).
Have any of the detox enzymes that metabolize estradiol been found to have these polymorphisms at higher frequencies in people with CFS?
Of these enzymes, so far the only one that has been reported to have been studied in CFS is COMT.
Goertzel et al. (26) found that they could distinguish CFS cases from controls with an accuracy of 75% by using combinations of polymorphisms of only five genes. They reported that of the nine genes containing a total of 28 polymorphisms that they considered, the gene for COMT was among the three most important genes for distinguishing CFS cases from controls. They considered six COMT polymorphisms in their study. (This result is remarkable in view of the facts that the entire human genome contains about 25,000 genes and several million polymorphisms, and this demonstrates the importance of elevated frequencies of COMT polymorphisms in CFS.)
Two studies (27,28) have found the COMT Val 158 Met polymorphism to have significantly higher frequencies in people with fibromyalgia than in controls. (This may be relevant because of the high comorbidity between CFS and fibromyalgia.)
What about polymorphisms in the CYP and GST enzymes in CFS? Have they been observed at elevated frequencies?
Although no studies have yet been published about the frequencies of polymorphisms in the CYP enzymes or the glutathione transferases in CFS relative to controls, the author has received anecdotal reports from several people with CFS who have had these polymorphisms characterized, and trends in the data suggest high frequencies for these polymorphisms in CFS, also.
Conclusions
This hypothesis is consistent with known biochemistry, and in combination with the Glutathione Depletion—Methylation Cycle Block Hypothesis for the pathogenesis of chronic fatigue syndrome (19), it provides a plausible explanation for the observed higher prevalence of CFS in women, a feature that has heretofore not been explained.
This hypothesis is also consistent with available evidence concerning the elevated frequencies of polymorphisms in catechol-O-methyltransferase (COMT) in CFS.
Controlled study in people with CFS of the frequencies of polymorphisms in the other enzymes involved in the metabolism of estradiol appears to be warranted. Such study would test this hypothesis. It would also shed light on the pathogenesis of CFS, and perhaps on the pathogeneses of other disorders important in women’s health.
References
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