Lack of Growth Hormone

Based on a talk given by Dr Robert Bennett at the Fibromyalgia Conference 2002. By Kathy Longley BSc(HONS)

A lack of growth hormone is not something that immediately springs to mind when thinking of fibromyalgia. What has the hormone known for making us taller got to do with pain and fatigue for instance? Well, quite a bit it would seem according to research. Growth hormone is responsible for repairing and restoring any damage that occurs to the muscles and tissues during the normal rigours of every day life. It stimulates growth and development through the production of new proteins to repair muscle tears and to replace worn-out cells and tissues that have passed their sell-by date. A constant lack of it leads to these repairs being overlooked, allowing them to pile up over time causing discomforture and pain. It is like living in a body that is never fully MOT'd.

Growth hormone (GH) is created and stored in the pituitary gland, the body's master hormone-producing gland located in the brain. Its release into the bloodstream is prompted by the hormone GHRH (growth hormone releasing hormone) secreted by the hypothalamus (see figure 1). Once in the bloodstream growth hormone acts on the liver to stimulate the release of its working partner IGF-1. It is IGF-1 that carries out the hard work of repairing and restoring the tissues and as its levels rise growth hormone itself is rapidly broken down and fades from the bloodstream. For this reason researchers measure IGF-1 levels in the blood, which faithfully reflect the amount of growth hormone released.

Growth hormone deficiency and fibromyalgia

Adults deficient in growth hormone have symptoms alike to fibromyalgia, for example, low energy, muscle weakness, impaired cognition, cold intolerance and a reduced exercise capacity. This overlap has led researchers like Dr Bennett to investigate growth hormone's activity in fibromyalgia patients. In 1992, Dr Bennett and Dr Clark measured plasma levels of IGF-1 in 70 female fibromyalgia patients and 55 controls (1). They reported significantly lower levels of IGF-1 in the majority of fibromyalgia patients, which was backed up by a similar study involving 500 fibromyalgia patients in 19972. Then in 1998 they conducted the first double blind, placebo controlled growth hormone replacement study in twenty-five patients with fibromyalgia (3).

The 25 patients were regularly injected with growth hormone and compared to another 25 patients injected with a placebo. Those receiving growth hormone showed a prompt increase in IGF-1 levels sustained throughout the nine-month trial and showed a significant improvement in their symptoms compared to the placebo group. Also, due to growth hormone therapy being very expensive some patients were unable to continue treatment after the completion of the study and complained of a relapse in their symptoms, further supporting the idea that low levels of growth hormone play a role in fibromyalgia.

What is the possible cause for this decline in growth hormone noted in fibromyalgia patients? Growth hormone is known to decline naturally in adults as they age, but fibromyalgia patients appear to be chronologically 33 years older in terms of their growth hormone levels (1).

The disruption of growth hormone release during deep sleep

The researcher Moldofsky was the first to notice in 1975 that deep sleep, known as stage 4-delta sleep, was interrupted by an intrusion of alpha waves in the majority of his fibromyalgia patients. He suggested that this disruption was responsible for the non-refreshing sleep and muscle pain reported in fibromyalgia. It is interesting that his control group developed similar symptoms when deprived of deep sleep, which were fully resolved following a night of undisturbed sleep, further supporting his theory. Other studies, for example, by Paiva (4) in 1994 and a recent study by Moldofsky (5) in 1998 have since supported these findings.

80% of growth hormone is released in a pulsatile fashion during deep sleep and its release is believed to be severely disrupted due to the alpha intrusion.

The Inhibitory Hormone - Somatostatin

Growth Hormone ChartThe control of growth hormone release is naturally more complex than portrayed in figure 1.

 In fact, growth hormone is the only pituitary hormone that receives both stimulatory and inhibitory signals from the hypothalamus. The inhibitory hormone involved is called somatostatin and for growth hormone to be released the levels of GHRH need to exceed the levels of somatostatin (see figure 2).

 It is beginning to become evident that levels of somatostatin are higher than normal in fibromyalgia and this hormone could be responsible for the growth hormone deficiency observed. Experiments, like those undertaken by Leol-Cerro6 in 1999, have demonstrated that when fibromyalgia patients are stimulated with GHRH they produce a normal growth hormone response. This indicates that growth hormone is being created and stored correctly in the pituitary gland, but is not being released adequately. Other reports have not yet confirmed these results, however an interesting experiment carried out by Dr Bennett (7) lends support to the somatostatin theory.

Growth Hormone ChartIn this experiment a group of fibromyalgia patients and healthy controls were asked to exercise to the point of exhaustion using a treadmill, which is used as a standard test of growth hormone release. In contrast to the healthy controls, the fibromyalgia patients did not produce the expected growth hormone response to exercise. However, when the fibromyalgia patients were given a drug called pyridostigmine one hour before the exercise program commenced, it was found that they were able to generate a reasonable growth hormone response. The drug pyridostigmine works by inhibiting the hormone somatostatin and therefore this experiment indicates that when the inhibitory effect of somatostatin is decreased fibromyalgia patients are able to release satisfactory amounts of growth hormone.

The researchers Neeck and Riedel (8) have put forward the idea that the multiple hormonal disturbances observed in fibromyalgia could be explained by elevated levels of the key stress hormone CRH (cortiotropin releasing hormone). CRH is known to increase the levels of somatostatin, which links it directly to suppressing growth hormone release. High levels of CRH can also lead to reduced levels of thyroid hormone and oestrogen and increased levels of prolactin and the stress hormone ACTH, which have all been observed to some extent in fibromyalgia patients (8). Some contradictory evidence for this idea is the low level of cortisol observed. Elevated levels of CRH and ACTH should stimulate high levels of cortisol; however, research reports low 24-hour urinary cortisol levels. Dr Bennett suggested in his talk that fibromyalgia patients have possibly reached the third and final stage of the stress response, namely exhaustion. In this state, prolonged high levels of CRH can cause the release of cortisol to become blunted, which would account for the low cortisol levels observed.

Conclusion

A persistant lack of growth hormone is an important issue and most likely responsible for the high percentage of muscle microtraumas in fibromyalgia contributing to the on going muscular pain. The low levels of growth hormone in fibromyalgia patients could be the result of high levels of the hormone somatostatin suppressing growth hormone release. The stress hormone CRH could be at the root of this disruption.

The abnormalities recorded in stage 4-delta sleep in a large number of fibromyalgia patients

could also largely contribute to the disruption of growth hormone released during the night.

Further research studies are required to determine and confirm the cause for growth hormone deficiency observed. Discovering new ways to tackle this deficiency could lead to effective drug therapy and an alleviation of some of the symptoms of fibromyalgia as indicated in Dr Bennett's study with growth hormone replacement therapy.

References
1. Bennett & Clark 1992, Arthritis and Rheumatism 35:10; 1113-1116. "Low levels of somatomedin C in patients with FM"
2. Bennett & Clark 1997, Journal of Rheumatology 24: 7; 1384-1389. "Hypothalamic-pituitary-IGF-1 dysfunction in patients with FM."
3. Bennett & Clark 1998, American Journal of Medicine 104:227-231. "A randomised, double-blind, placebo controlled study of growth hormone in the treatment of fibromyalgia."
4. Paiva et al 1994, Journal of Rheumatology 21:1113-7. "Sleep cycles and alpha-delta sleep in FMS."
5. Moldofsky 2001, American College of Rheumatology Jan 25th pp222-230. "Sleep cycles characteristics in FM."
6. Leol-Cerro et al 1999, Journal of Clinical Endocrinology Metabolism 84:3378-3381. "GHRH-GH-IGF-1 axis in FM."
7. Bennett et al 2002, Arthritis & Rheumatism (In Press) "Impaired growth hormone secretion in fibromyalgia patients: evidence for augmented hypothalamic somatostatin tone."
8. Neeck & Riedel 1999, Annuals of New York Academy of Science 876:325-38; "Hormonal perturbations in fibromyalgia syndrome."
Copyright © K.E Longley 2002

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