Stress 179an increased risk of developing arthritis and musculoskeletal
conditions.
Besides the epidemiological data, there is considerable
evidence to support a role of reproductive hormones in the
development of RA (for review, see Grossman, Roselle, &
Mendenhall, 1991). Early observations of pregnant women
with RA revealed that the women typically developed remis-
sion of RA activity during the third trimester, only to experi-
ence relapses postpartum (Hazes, 1991; Persellin, 1977).
Other research has demonstrated that nulliparious women are
at greater risk for developing RA (Hazes, 1991). Finally,
reproductive hormones have been found to have immune
stimulating and suppressing effects. For instance, the repro-
ductive hormones prolactin and estrogen are presumed
to have immunoenhancing effects (Jorgensen & Sany,
1994). Furthermore, prolactin suppresses cortisol secretion
(Jorgensen & Sany, 1994). The immunostimulatory effects of
prolactin coupled with suppressed cortisol may partially ex-
plain the relapse of RA postpartum, when prolactin levels are
elevated. Thus, there may exist an association between repro-
ductive hormones and arthritis activity via the effects on
the immune system. Despite the promise of this hypothesis,
few studies have investigated the relationship. However, one
study found that, when confronted with interpersonal stres-
sors, women with RA displayed greater increases in im-
munostimulatory hormones such as prolactin and estrogen
than women with OA (Zautra et al., 1994). Furthermore,
these increases in prolactin and estrogen were associated
with clinicians• ratings of arthritis disease activity. Overall,
these results support a central role of reproductive hormones
in the RA disease activity.
Fewer studies have investigated the role of reproductive
hormones in OA. However, the established protective effect
of osteoporosis (which is associated with low estrogen lev-
els) on development of OA suggests that there may exist a
link between reproductive hormones and OA (for review,
see Sambrook & Naganathan, 1997). However, it is also fea-
sible the negative association between osteoporosis and OA
is due to a spurious variable such as body mass; women with
osteoporosis tend to weigh less, whereas OA is associated
with obesity.
As in RA and OA, there is also preliminary evidence to sug-
gest a relationship between FM and reproductive hormones.
The greater prevalence of FM in women than men supports a
role of female reproductive hormones in the development of
FM (Lawrence et al., 1998). In addition, like RA, there is evi-
dence that FM symptoms worsen during the third trimester of
pregnancy and the postpartum period (Ostensen, Rugelsjoen,
& Wigers, 1997). Furthermore, in one study, investigators
compared the prevalence of FM in women with clinically high
levels of prolactin to women with normal levels of prolactin
(Buskila et al., 1993). Results revealed that 71% of the women
with elevated prolactin levels met diagnostic criteria for FM,
whereas less than 5% of the women with normal prolactin lev-
els met this criteria. Finally, results of some studies revealed
elevated basal prolactin levels (Griep et al., 1994) and exag-
gerated prolactin responses to hormonal challenges in women
with FM compared to healthy women, although not all studies
demonstrated these differences (Korszun et al., 2000). Over-
all, these results suggest that, as in individuals with RA, in-
dividuals with FM may have elevated levels of prolactin. As
prolactin promotes in”ammatory processes, these results
imply an in”ammatory process in FM. However, since there is
currently no direct evidence of in”ammation in FM, this con-
clusion is putative.The Immune SystemAlthough we have discussed the indirect effects of stress
on immunity via the endocrine and nervous systems, the
immune system reciprocally affects the endocrine and ner-
vous systems. When the immune system is activated, a cell-
mediated immune response ensues to activate T cells that
attack •foreignŽ cells. Activated T cells also release a series
of chemical mediators to stimulate more T cell, B cell, and
macrophage activity. Activated macrophages then release a
series of chemicals called interleukins, which are also called
cytokines. Although there are many interleukins, for the
purposes of this chapter we primarily focus on interleukin-1
(Il-1), interleukin-2 (Il-2), and interleukin-6 (Il-6). These
cytokines in turn stimulate further in”ammatory processes.
Autoimmunity occurs when the body•s immune system
mistakes its own tissue as foreign (i.e., an antigen) and initi-
ates an immune response to destroy it. In the case of RA, the
immune system attacks the synovial lining of the joints.
Investigators have identi“ed at least one mechanism by
which this process occurs. In some RA patients, an acute in-
fection causes the immunoglobulin-G (IgG) antibody to mu-
tate. The immune system then mistakes this mutated antibody
for an antigen and mounts an attack against it (for review, see
Mageed, Borretzen, Moyes, Thompson, & Natvig, 1997).
During this attack, immunoglobulin-M (IgM) antibody binds
to the mutated IgG antibody, creating a bound complex com-
monly referred to as rheumatoid factor (RF; Mageed et al.,
1997). Although RF is not found in all RA patients, there is
some evidence that RF-positive and RF-negative RA patients
may differ in degree of life stress. For instance, Stewart,
Knight, Pakmer, and Highton (1994) found that RF-negative
RA patients experienced more life stress prior to onset of RA
symptoms than their RF-positive counterparts.