HPA Axis & Fibromyalgia


HPA Axis and FibromyalgiaRecent research has begun to narrow down the historically long list of possible causes of fibromyalgia. While many researchers believe that fibromyalgia is likely caused by the malfunction of the body’s internal pain processing system, other potential factors continue to generate interest as possible culprits.

One such factor is the hypothalamic-pituitary-adrenal axis, or HPA axis, which refers to the complex interactions that transpire between the body’s central nervous system and stress hormones. Essentially, the HPA axis is a feedback loop through which signals that are sent by the brain stimulate the release of hormones that are necessary in order for the body to respond to stress. In its most basic form, the HPA axis works like this: The hypothalamus in the brain releases a hormone known as CRH, which then causes the pituitary gland to release the hormone ACTH into the bloodstream. From there, ACTH sends a signal to the adrenal glands to release a number of other hormonal compounds, including epinephrine (i.e., adrenaline), norepinephrine, and cortisol. Together, these three hormones allow the body to respond to a threat, by increasing blood pressure and heart rate, increasing blood flow to the muscles, and improving reaction time. Blood sugar levels also rise to provide extra fuel to the body. Once the body no longer senses that a threat is present, cortisol sends a feedback signal to the hypothalamus to stop producing CRH, which  essentially shuts downs the stress response.

Although the underlying way in which the HPA axis operates is identical among all individuals, the magnitude of the stress response can vary considerably from one person to another. For example, in most people, the HPA axis functions appropriately enough to allow the body to respond to a threat; however, some individuals may not have a strong enough response while others may over-respond. The factors that contribute to this variation are likely genetic and/or environmental in nature.

A number of conditions have been linked, or are presumed to be associated with, an overactive or underactive HPA axis. Gastrointestinal disorders, immune deficiency, depression, chronic fatigue syndrome, and chronic pain disorders – including fibromyalgia – have all been studied in association with the HPA axis. While the exact role that the HPA axis plays in the development of fibromyalgia symptoms is not known, research suggests that such a link exists. Further study of the relationship between the HPA axis and fibromyalgia is likely to lead to a better understanding of the nature of fibromyalgia itself, as well as more effective treatment options for those who suffer from it.Treating Dysfunctional HPA Axis

HPA Axis and Fibromyalgia Research

Research papers related to fibromyalgia and the HPA axis first began to appear in the medical literature in the early 1990s. Since that time, a number of studies have been published that examine this relationship from a variety of angles. An early study by Griep et al. (1993) evaluated the HPA axis activity of 10 female patients with fibromyalgia and 10 healthy control subjects. Following a number of tests designed to measure levels of CRH, glucose, and ACTH in the clinical setting, the study found that patients with fibromyalgia had a much greater HPA axis reactivity than the control subjects. These findings led the researchers to conclude that patients with fibromyalgia might in fact suffer from adrenal gland insufficiency, which could be related to their impaired muscle performance.

The following year, Neeck and Riedel (1994) published a review article addressing the neurological and hormonal disturbances that were known at the time to be associated with fibromyalgia. Their review touched on the possible role that a malfunctioning central nervous system might have in the onset of fibromyalgia-related muscle pain, as well as the cascade of symptoms that appear as a result of decreased levels of serotonin that had been shown among fibromyalgia patients. The authors suggested that these circumstances might be the culmination of chronic stress placed on the body, and that the resulting abnormalities of the HPA axis might indicate the body’s attempt to restore homeostasis (i.e., stability). A later review by Crofford and colleagues (1996) discussed the major observations to date related to stress response dysfunction in fibromyalgia patients, and noted that the common clinical features (widespread pain, fatigue) fibromyalgia shares with other comorbid conditions, may be related to an underlying dysfunction of the HPA axis.

In the years that followed, more researchers began to prospectively evaluate the role that a malfunctioning HPA axis might have in the development of the characteristic symptoms of fibromyalgia. Crofford et al. (1994) studied 12 fibromyalgia patients and 12 control subjects and found significant differences in the interactions between cortisol and CRH among fibromyalgia patients, as well as non-significant, yet highly variable differences among other hormones. Griep and colleagues also published findings of a study in 40 fibromyalgia patients and 12 healthy control subjects. Like prior studies, these researchers found that the HPA axis was dysfunctional in fibromyalgia patients, who often had low cortisol levels, hyperactive release of ACTH and CRH, and resistance to feedback that would stop the stress response (Griep et al. 1998). Other researchers have continued to find similar prospective evidence to support the role of a malfunctioning HPA axis in fibromyalgia (Torpy et al. 2000; Kirnap et al. 2001; Calis et al. 2004; Mutsuura et al. 2009).

Despite the mounting evidence to suggest the role of the HPA axis in fibromyalgia, an article published by Geenen et al. in 2002 suggested that hormone therapy was likely not a therapeutic alternative for most patients. The authors cited the fact that most studies evaluating the role of the HPA axis in fibromyalgia were small, as well as the observation that many reported hormone level deviations were not severe. They concluded with the generalized recommendation that for patients who have hormone levels in the lower part of the normal range, interventions directed toward controlling pain, improving fatigue and exercise capacity, regulating sleep, and improving mood disturbances might indirectly improve hormone functioning.

More recently, a study by Bonifazi et al. (2006) evaluated the effects of a three week multidisciplinary non-drug treatment program that included individually-tailored aerobic exercise and cognitive-behavioral therapy on fibromyalgia symptoms and HPA axis functioning. The 12 patients who were included in this study were shown to have improved aerobic capacity at the end of the treatment period, as well as a sharp decline in their cortisol levels over time. Furthermore, the patients experienced a decrease in the number of positive tender points, pain, and depressive symptoms following treatment. The authors concluded that one of the likely factors contributing to the positive effectives of this therapeutic regimen was improvement in the patients’ HPA axis functioning.

Recently published studies have investigated the role that depression plays in HPA axis-related dysfunction in fibromyalgia (Wingenfeld et al. 2010), while others have posited that other neurobiological mechanisms other than reduced cortisol, may be responsible for the symptoms associated with fibromyalgia (Geiss et al. 2012).



1.        Bonifazi M, Suman AL, Cambiaggi C, Felici A, Grasso G, Lodi L, Mencarelli M, Muscettola M, Carli G. Changes in salivary cortisol and corticosteroid receptor-alpha mRNA expression following a 3-week multidisciplinary treatment program in patients with fibromyalgia. Psychoneuroendocrinology. 2006;31(9):1076-86.

2.        Calis M, Gökçe C, Ates F, Ulker S, Izgi HB, Demir H, Kirnap M, Sofuoglu S, Durak AC, Tutus A, Kelestimur F. Investigation of the hypothalamo-pituitary-adrenal axis (HPA) by 1 microg ACTH test and metyrapone test in patients with primary fibromyalgia syndrome. J Endocrinol Invest. 2004;27(1):42-6.

3.        Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Michelson D, Kling MA, Sternberg EM, Gold PW, Chrousos GP, Wilder RL. Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia. Arthritis Rheum. 1994;37(11):1583-92.

4.        Crofford LJ, Engleberg NC, Demitrack MA. Neurohormonal perturbations in fibromyalgia. Baillieres Clin Rheumatol. 1996;10(2):365-78.

5.        Geenen R, Jacobs JW, Bijlsma JW. Evaluation and management of endocrine dysfunction in fibromyalgia. Rheum Dis Clin North Am. 2002;28(2):389-404.

6.        Geiss A, Rohleder N, Anton F. Evidence for an association between an enhanced reactivity of interleukin-6 levels and reduced glucocorticoid sensitivity in patients with fibromyalgia. Psychoneuroendocrinology. 2012;37(5):671-84.

7.        Griep EN, Boersma JW, de Kloet ER. Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome. J Rheumatol. 1993;20(3):469-74.

8.        Griep EN, Boersma JW, Lentjes EG, Prins AP, van der Korst JK, de Kloet ER. Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain. J Rheumatol. 1998;25(7):1374-81.

9.        Kirnap M, Colak R, Eser C, Ozsoy O, Tutus A, Kelestimur F. A comparison between low-dose (1 microg), standard-dose (250 microg) ACTH stimulation tests and insulin tolerance test in the evaluation of hypothalamo-pituitary-adrenal axis in primary fibromyalgia syndrome. Clin Endocrinol (Oxf). 2001;55(4):455-9.

10.     Mutsuura H, Kanbara K, Fukunaga M, Yamamoto K, Ban I, Kitamura K, Nakai Y. Depression and anxiety correlate differently with salivary free cortisol in the morning in patients with functional somatic syndrome. Appl Psychophysiol Biofeedback. 2009;34(4):291-8.

11.     Neeck G, Riedel W. Neuromediator and hormonal perturbations in fibromyalgia syndrome: results of chronic stress?

12.     Baillieres Clin Rheumatol. 1994;8(4):763-75.

13.     Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia. Arthritis Rheum. 2000;43(4):872-80.

 Wingenfeld K, Nutzinger D, Kauth J, Hellhammer DH, Lautenbacher S. Salivary cortisol release and hypothalamic pituitary adrenal axis feedback sensitivity in fibromyalgia is associated with depression but not with pain. J Pain. 2010;11(11):1195-202.

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