Scand J Rheumatol 2000;29 Suppl 113:8±12

Neuroendocrine and hormonal perturbations and relations to the

serotonergic system in ®bromyalgia patients

Gunther Neeck

Department of Rheumatology, Kerckhoff Clinic and Foundation, Bad Nauheim, Germany

The symptomatology of the ®bromyalgia syndrome (FMS) often resembles an alteration in central nervous set points at least in three
systems. The patiens suffer under chronic pain in the region of the locomotor system, presumably re¯ecting a disturbed central processing of
pain. Anxiety and depression often characterizes the clinical picture. Almost all of the hormonal feedback mechanisms controlled by the
hypothalamus are altered. Characteristic for FMS patients are the elevated basal values of ACTH, follicle-stimulating hormone (FSH), and
cortisol as well as lowered basal values of insulin-like growth factor 1 (IGF-1, somatomedin C), free triiodothyronine (FT3), and oestrogen.
In FMS patients, the systemic administration of the relevant releasing hormones of corticotropin-releasing hormone (CRH), growth
hormone-releasing hormone (GHRH), thyreotropin-releasing hormone (TRH), and luteinizing hormone-releasing hormone (LHRH) leads
to increased secretion of ACTH and prolactin, whereas the degree to which TSH can be stimulated is reduced. The stimulation of the
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hypophysis with LHRH in female FMS patients during their follicular phase results in a signi®cantly reduced LH response. All in all, the
typical alterations in set points of hormonal regulation that are typical for FMS patients can be explained as a primary stress activation of
hypothalamic CRH neurons caused by the chronic pain. In addition to the stimulation of pituitary ACTH secretion, CRH activates
somatostatin on the hypothalamic level, which in turn inhibits the release of GH and TSH on the hypophyseal level. The lowered oestrogen
levels could be accounted for both via an inhibitory effect of the CRH on the hypothalamic release of LHRH or via a direct CRH-mediated
inhibition of the FSH-stimulated oestrogen production in the ovary.
Serotonin (5HT), precursors like tryptophan (5HTP), drugs which release 5HT or act directly on 5HT receptors stimulate HPA axis,
indicating a stimulatory serotonergic in¯uence on HPA axis function. Therefore activation of the HPA axis may re¯ect an elevated
serotonergic tonus in the central nervous system of FMS patients.

Key words: ®bromyalgia, HPA axis, serotonergic system

For personal use only.

Pain, life stresses, and the ®bromyalgia syndrome
In attempting to sum up the current literature there
is a tendency to localize the primary disorder
underlying ®bromyalgia syndrome (FMS) in the
central nervous system (1). A reduced pain threshold
on the level of the central nervous system (2) appears
the primary cause of a whole cascade of further
disorders, with various autonomic dysfunctions,
psychic changes (3), and a painful, unrelaxed
musculature (4) with changes which can be demon-
strated ultrastructurally (5). The very early stages of
the disease often involve a biomechanically-caused
local pain syndrome, chie¯y in the area of the axial
skeleton (6). However, this local problem occurs
against the background of a clearly altered sensitiv-
ity of the central nervous processing of periphereal
pain stimuli, this being due either to genetic causes
(7), early traumatisations with severe stress events (8)
or both. As a consequence, the pain spreads beyond
the original localization to encompass increasingly
widespread areas of the locomotor system. The
mechanisms underlying this development of myo-
fascial wide spread pain are still unknown. Changes
in the neurotransmitter systems of substance P and
Gunther Neeck, Department of Rheumatology, Kerckhoff Clinic
and Foundation, Ludwigstrasse 37 ± 39, DE-61231 Bad Nauheim,
Germany.
serotonin at spinal cord level and higher centers has
been proposed (9). Overall it is becoming increasing
clear that the de®ciency of a single neurochemical
substance is not the cause of ®bromyalgic symto-
matology, but rather that a whole series of altera-
tions of the set points in the central nervous system
are the correlate of ®bromyalgia with the con-
sequence of changed reactivity of the neuroendo-
crinium (10). Fibromyalgia patients, namely, not
only show a reduced threshold for pain stimuli, but a
generally heightened sensitivity to stressful in¯uences
of various kinds. The term `stress' is complex and
poorly de®ned to date. However, since his initial
description by Hans Selye, it has becoming increas-
ing evident that the hypothalamus-hypophysis-adre-
nal cortex axis plays a central role in the stress
response. Activation of neurons which produce the
corticotropin-releasing hormone (CRH) in the
hypothalamus has direct effects on CRH receptors
in the brain and not only stimulates the axis
hypophysis-adrenal cortex, but, via, e.g., somato-
statin, also a whole concert of further hypothalamic-
hypophyseal interactions with a permanent effect on
the regulation of peripheral glands, too (11) (Fig. 1).
A wide range of different stimuli can activate the
CRH-producing neuronsÐalongside painÐvarious
cytokines, such as interleukin-1, interleukin-6, and
tumor-necrosis factor in particular. In so-called 'post

8 # 2000 Scandinavian University Press on license from Scandinavian Rheumatology Research Foundation
 Neuroendocrine and hormonal perturbations in ®bromyalgia patients
Fig. 1. CRH driven hypothalamic hypophyseal interactions
(incomplete): the overactivity of CRH neurons driven by stress
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induces a typical hormonal pattern in FMS patients. CRH sti-
mulates ACTH and Cortisol. CRH stimulates also SOM at the
hypothalamic level which inhibits the release of GH and TSH.
Low GH levels induce low IGF-1 production and low TSH low
levels of thyroid hormone levels, especially T3. Via negative
feedback mechanisms hypothalamic TRH is elevated which sti-
mulates prolactin. Prolactin suppresses the secretion of LHRH
with the consequence of low LH and estrogen.
Abbreviations: CRH (Corticotropin-Releasing Hormone), TRH
(Thyrotropin-Releasing Hormone), LHRH (Luteinising-Hor-
mone-Releasing Hormone), ACTH (Adrenocorticotropic Hor-
mone), GH (Growth Hormone), SOM (Somatostatin), TSH
(Thyro-Stimulating Hormone), PRL (Prolactin), LH (Luteinising
For personal use only.
Hormone), FSH (Follicle-Stimulating Hormone), IGF-1 (Insulin
Like Growth Factor), Estr (Estrogen).
traumatic stress disorders too, the change in the
reactivity of the HPA axis appears to play an
important role. The acute stress event has long
passed but the CRH-producing neurons of the
hypothalamus respond to comparatively banal
stimuli of everyday life with a stress reaction. These
individuals are, therefore, not only more prone to
stress in a psychological sense, but also in a
biological sense. Fibromyalgia patients who have
suffered sexual abuse or been the victims of torture
could be subject to such mechanisms. In his theory
`Diseases of Adaption', Hans Selye (12) describes
disease as caused either by hyperfunction or
hypofunction of the axis hypophysis-adrenal cortex.
Interestingly, it is becoming increasingly clear that
chronic fatique syndrome is characterized more by
hyporeactivity and ®bromyalgia in contrast by
hyperreactivity of the HPA axis (13).
Set point alterations in the stress-processing
neuroendocrine system
The symptomatology of FMS encompasses three
systems. First chronic pain in the musculoskeletal
system, which is presumably mediated by a dis-
turbance in the central mechanism responsible for
processing pain stimuli. Secondly the endocrinal
regulation is considerably impaired, for almost all
hormonal feedback systems are altered. And third
anxiety and depression are often the most prominent
psychic symptoms. Based on this symtomatology, it
is often assumed that the disease is primarly of
central nervous system origin (14, 15). Stress
resulting from either psychic or somatic traumata
appears to be the most common factor which leads
to the development of FMS, which is the reason why
FMS is often also described as a ``stress-dependent
syndrome'' (16). However, stress is an imprecisely
de®ned concept in terms of modern methodology, it
is dif®cult to quantify, and the central nervous
system mechanisms by which stress produces organic
symptoms and signs remain largely unexplained.
Via afferent connections, which are also largely
unknown, stress induces an activation of various
hypothalamic neurons, of which the CRH-producing
and antidiuretic hormone-producing neurons are the
most important and well-investigated (17, 18). Acute
psychic stress is also usually associated with elevated
ACTH and cortisol levels. In FMS patients, elevated
cortisol values are also frequently correlated with the
degree of severity of the depression (15); but it is
unclear however whether the depression develops as
a reaction to the chronic pain or represents an
independent disease within the FMS. However, the
disturbed hormonal regulation occurring with FMS
manifests itself not only in the hormones of the
hypothalamus-hypophysis-adrenal cortex axis. All of
the symptoms and signs of hypothyreosis are very
frequently observed in FMS patients (19, 20). The
regulation of the release of growth hormone also
seems to be disturbed in FMS patients, for one often
®nds clearly lowered IGF-1 values (21). Studies of
the hormonal pro®le of FMS patients employing
stimulation of the various hormonal axes via the
concomitant systemic injection of the hypothalamic
releasing hormones CRH, TRH, GHRH, and
LHRH have con®rmed the ®ndings reported in the
literature and, in addition, provided evidence of a
disturbed regualtion of sex hormone production in
female FMS patients, above all that of oestrogen
(22). The stereotyped hormonal pro®le found with
FMS also provides support for the assumption that
the syndrome involves an integrated hormonal
regulation to a common disorder. From this
perspective, it is rather unlikely that disturbances
of the individual hormonal axes play a causal role in
FMS, but rather that the disturbance of the
hormone balance is more appropriately regarded
as the result of a reaction of the central nervous
system (CNS) to the main symptom of the FMS,
namely, to the chronic pain in the musculoskeletal
system.
9
 G. Neeck

Central role of the CRH-producing neurons of the the hypothalamic level, reduces the gonadal function
hypothalamus via the inhibition of LHRH secretion (30, 22, 31).
Chronic stress is also often accompanied by lowered
Although the site of the transformation of the pain
LH values (32). Recently, it could be shown that
signals in the CNS is not precisely localizable, it is
receptors for CRH are expressed in the ovary and
nevertheless regarded as established that the stress
CRH inhibits the FSH-stimulated oestrogen produc-
and pain signals reach the limbic system, which
tion (33).
exerts both activating and inhibitory effects on CRH
neurons. Apparently, the activating in¯uences pre-
dominate during stress and pain. Besides its clas- Role of CRH in producing depression and anxiety
sic effect on the pituitary pro-opiomelanocortin
The symptomatology of anxiety and depression is
(POMC)-producing cells and the release of ACTH,
frequently observed in FMS patients. In many cases,
CRH functions as a neurotransmitter to stimulate
treatment with antidepressants leads to a reduc-
numerous other CNS neurons. Additionally, numer-
tion in the number of the tender points and
ous periphereal cells possess receptors for CRH. For
other characteristic symptoms. Similarly to FMS,
example, it could be demonstrated (23, 24) that
depressed patients often show an increased cortisol
CRH increases the secretion of somatostatin in
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level (34). Another relevant ®nding is that depressed

hypothalamic and cortical neurons. Via the hypotha-
patients also react to the systemic administration of
lamic-pituitary portal system, somatostatin reaches
TRH with a reduced secretion of TSH and an
the hypophysis and inhibits the secretion of growth
increased release of prolactin (35). All of these
hormone and TSH (25 ± 27). Thus, this physiological
observations provide support for the supposition
mechanism offers an explanation for the observation
that these psychic disturbances are accompanied by
of lowered plasma IGF-1 and thyroid hormone
increased CRH activity. However, the view has
levels in FMS patients (21, 28, 10). The reduced
gained acceptance in recent years that the increased
sensitivity to stimulation by TSH in FMS patients
production of CRH may not only a concomitant
after systemic administration of the TRH can also be
symptom of anxiety or depression, but rather can be
accounted for by an elevated somatostatin level. In
ist cause (28, 36). Timpl et al. (37) have recently
For personal use only.

contrast, the lactotrophic cells of the hypophysis

have no somatostatin receptors. The cause of the
increased prolactin secretion resulting from systemic
administration of TRH in FMS patients is probably
the hypothyreosis, which would be expected to load
to increased TRH activity and, therefore, a chronic
stimulating effect on the lactotropic cells of the
hypophysis via the mechanism of negative feedback
on the hypothalamus.
Pro®le of the sex hormones in female patients with
®bromyalgia syndrome
Although the majority of FMS patients are women,
only few studies have considered the possibility of
the involvement of the sex hormones (29, 10). If the
FSH and oestrogen values of female FMS patients
are compared during the follicular phase with the
control group of women of the same age, signi®-
cantly lower oestrogen plasma values are found with
FMS in spite of an elevated FSH level. Furthermore,
the LH secretion is signi®cantly reduced in female
FMS patients after the systemic administration of
LHRH. An increased CRH activity caused by
chronic pain might also explain this phenomenon.
In clinical practice, it is often observed that stress
and chronic pain leads to a disturbance of gonadal
function; in this connection, it has been experimen-
tally demonstrated that CRH, and also prolactin on
demonstrated that a lack of CRH-1 receptors
(CRHr1) in speci®c areas of the brain drastically
reduces the physiological responses to stress as well
as the related anxiety reaction. This result is a clear
indication that CRHr1 represents a receptor for
stress. It can therefore be concluded from these
results that for FMS, and also for other diseases
with increased CRH activity including depression,
there might be a disturbance of the negative
feedback of glucocorticoids on the hypothalamus
which normally reduces increased CRH activity to
within normal limits.
Involvement of serotonin in regulation of pituitary-
adrenocortical function
An increased CRH activity may be additionally
in¯uenced also by other factors. Serotonin (5-HT)
plays a pivotal role in the regulation of the HPA
axis, too. In particular, 5-HT seems to be involved in
the stimulation of ACTH secretion during stress.
CRH-containing neurons projecting from the para-
ventricular nucleus to the median eminence, receive
synaptic input from serotonin neurons projecting
from the midbrain raphe nuclei. Serotonin stimulates
the release of bio- or immunoassayable CRH from
isolated rat hypothalamus in vitro (38).
A variety of drugs including precursors of 5-HT
such as tryptophan (5-HTP), drugs which release

10
 Neuroendocrine and hormonal perturbations in ®bromyalgia patients
5-HT such as fen¯uramine and drugs which act
directly on 5-HT receptors such as ipsapirone
increase cortisol and ACTH concentrations (39).
There is general assumption that such stimulation
occurs at the hypothalamic level. At least two
distinct serotonin receptor subtypes can mediate this
effect. One is the 5-HT1A receptor, and the other
seems to be a 5-HT2A receptor. Possibly, the 5-
HT2C receptor or other receptors can also mediate
these effects (40). But short-term effects should be
differentiated from long-term effects. Acute citalo-
pram as a selective serotonin reuptake inhibitor
activate the HPA-axis, but long-term citalopram
treatment desensitizes the HPA-axis, supporting the
hypothesis that the therapeutic effects of long-term
antidepressant treatment reduces HPA axis respon-
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siveness (41). Interestingly there exist sex differences
in the HPA axis responsiveness to stress: testosteron
desensitizes HPA axis function and inhibits seroto-
nergic activation (42).
The physiological role of the stimulatory seroto-
nergic in¯uence on HPA axis function is still not
completely understood, but serotonin may play a
role in circadian rhythmicity and HPA axis function
by certain types of stress. Measurement of ACTH or
cortisol levels in humans after administration of
directÐor indirectÐacting serotonin agonists and
For personal use only.
antagonists provides one means of probing the
functional state of brain serotonergic systems in
disease or after drug treatment (43). Therefore an
enhanced activity of the HPA axis in FMS patients
may also re¯ect an elevated serotonergic tonus
within the central nervous system. Drugs which
reduce the serotonergic tonus should be tested for
bene®cial effects in FMS patients.
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