178 Arthritis and Musculoskeletal Conditions
had higher cortisol levels than a healthy control group, there
were no differences in cortisol reactivity to acute stressors be-
tween the FM and RA groups (Catley et al., 2000).
While some studies have found trends toward cortisol
hypersecretion in FM patients, others have instead found hy-
persecretion of ACTH, with no dose-dependent increase in
cortisol (Crofford et al., 1994; Griep, Boersma, & deKloet,
1993). These results suggest a decreased responsiveness of
the adrenal cortex to ACTH, possibly as a result of down-
regulation of ACTH receptors. Furthermore, there is evi-
dence of a ”attened diurnal pattern of cortisol secretion in
FM patients compared to RA patients (Crofford et al., 1994).
Another recent study found reduced ACTH responses to
hypoglycemic stress in FM patients, suggesting hypoactivity
of the HPA axis (Adler et al., 1999). Thus, as in RA, there is
con”icting evidence for HPA dysregulation in RA and FM
patients.
In RA and FM, different neuroendocrine processes may
produce the cortisol hyposecretion common to both dis-
orders. For instance, in RA patients, cortisol may have been
chronically secreted due to the chronic in”ammatory process
of RA. To compensate for these chronically elevated cortisol
levels, other systems, including those that regulate the im-
mune system, may become increasingly less sensitive to cor-
tisol through down-regulation of cortisol receptors. The net
result would be normal or relatively low cortisol levels for a
given level of in”ammation. In contrast, depression is not
only associated with elevated cortisol levels (Deuschle,
Weber, Colla, Depner, & Heuser, 1998), but is often comor-
bid with FM. As a result, of the chronically elevated levels of
cortisol associated with depression in FM, glucocorticoid
receptors may have down-regulated. Thus, patients with RA
and FM may both have cortisol hyposecretion, but from dif-
ferent causes.
SAM Axis
Stress can affect health via pathways other than the HPA axis.
The SAM axis is part of the sympathetic nervous system and
is responsible for initiating the •“ght-or -”ightŽ response
(Cannon, 1932). Whereas the HPA axis is primarily an en-
docrine system (i.e., hormones travel through the blood-
stream), the SAM axis is neuroendocrine, consisting of both
neural and endocrine tissues. In the SAM axis, stress stimu-
lates nerves that directly innervate the adrenal medulla,
which in turn releases norepinephrine (NE) and epinephrine
(EPI) into the bloodstream (Figure 8.1). Like the HPA axis,
the SAM axis has immunomodulating effects. Whereas the
HPA axis inhibits the in”ammatory response, the SAM axis
activates it (Madden & Livnat, 1991). As nervous impulses
directly stimulate the adrenal medulla, the SAM axis has
much faster and more immediate effects than the slower act-
ing HPA axis.
There is some evidence for SAM dysregulation in RA.
Some investigators believe that the cycle of in”ammation in
RA re”ects hypersecretion of pro-in”ammatory hormones
with the SAM axis serving an immunostimulating function
(Madden & Livnat, 1991). Indeed, results of some studies
suggest SAM hyperactivity in RA. For instance, one study
found that RA patients had higher plasma NE and EPI levels
than healthy controls (Lechin et al., 1994). Another study
found down-regulation of beta-2 receptor density on periph-
eral blood mononuclear cells in RA, which may be a result of
chronically elevated sympathetic activity (Baerwald, Graefe,
Muhl, von Wichert, & Krause, 1992).
As with HPA axis dysregulation, evidence of SAM
dysregulation in RA is far from conclusive. Just as results of
several studies have suggested SAM hyperactivity, still
others have presented evidence for SAM hypoactivity in RA.
Although not exclusively due to SAM activity, blood pres-
sure and heart rate are often used as indices of SAM activity.
For instance, in a study of recently diagnosed RA patients,
Geenan, Godaert, Jacobs, Peters, and Bijlsma (1996) found
that blood pressure was negatively related to pain severity. In
another study, compared to healthy controls, RA patients had
lower heart rate and blood pressure responses to a cognitive
stress test, although levels still fell within normal limits
(Geenan et al., 1998). The authors of those studies suggest
that, since the SAM axis stimulates the immune system,
SAM hypoactivity may have developed over time as a means
to minimize the in”ammation present in RA.
Investigators have also begun to examine the role of SAM
activity in FM (Mengshoel, Saugen, Forre, & Vollestad,
1995; van Denderen, Boersma, Zeinstra, Hollander, & van
Neerbos, 1992). The few preliminary investigations of cross-
sectional differences between urinary catecholamine secre-
tion in FM and healthy controls (with no stress conditions)
have suggested a trend toward increased NE in FM patients
(Yunus, Dailey, Aldag, Masi, & Jobe, 1992).Reproductive SystemThe greater prevalence of arthritis and other musculoskeletal
conditions in women than men has led investigators to hy-
pothesize a role of reproductive hormones in these disorders.
Although men also experience hormonal changes with aging,
women endure a dramatic decrease in reproductive hormones
such as estrogen, progesterone, and gonadotropins such
as follicle-stimulating hormone and luteinizing hormone.
This decline in reproductive hormone levels coincides with