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Hormone Therapies: Newest Advance in Pain Care

Severe, uncontrolled pain may exhaust the adrenal gland, resulting in low levels of pregnenolone and cortisol. While adequate pain control will usually normalize serum hormone levels, opioid-induced suppression of the system may require additional treatment.
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The effect of severe, persistent pain on the hormone system is profoundly negative.1-5 If the patient’s hormone system is not kept homeostatic and balanced, the patient with pain will rapidly age and deteriorate. Episodic excess of cortisol in the blood, which occurs during pain flares, is particularly deleterious. Consequently, the achievement of hormonal balance—not too high or too low—has to be a primary goal of treatment.

Unfortunately, some of the potent pain medications, particularly opioids, may suppress the production of some adrenal and gonadal hormones, especially testosterone and pregnenolone, and need to be replaced.6-10 If any major adrenal or gonadal hormone becomes deficient during ongoing opioid treatment, the patient likely will not respond well to the prescribed pain medication and may report and exhibit such symptoms as poor pain control, depression, mental impairment, insomnia, allodynia, and hyperalgesia. The combined effect of pain per se and opioid-induced suppression on the hormonal system must be thoroughly understood by pain practitioners.

In addition to replacing those hormones that become depleted during therapy, some specific hormones have anabolic and regenerative properties and are emerging as effective adjuncts in advancing pain care.11-13 They can be easily and safely prescribed by any pain practitioner. Reported here is a summation of the deleterious effects of pain on the hormone system, as well as those hormones that have the potential to promote regenerative and permanent pain reduction.


Basic Hormone Functions

The basic functions of hormones are worth reviewing, as they clearly reveal why pain management practitioners should be interested in their biologic effects (see Table 1). First, hormones regulate cellular metabolism. Included here are insulin and thyroid. Second, they mediate the inflammatory response to promote healing. Included here are pregnenolone, progesterone, and cortisol. Third, certain hormones cause tissues to grow. Included here are androstenedione, dehydroepiandrosterone, and testosterone. Relative to pain relief, adrenal and gonadal hormones have two other functions. They migrate from the glands and help to provide pain relief as well as serve many emotional and intellectual functions.14-26

Table 1. Basic Functions of Hormones

Production of Hormones

Figure 1 shows the biochemical pathway for the production of hormones in the adrenal and gonad glands. All hormones have pregnenolone and progesterone as basic precursors. Pregnenolone is derived from cholesterol circulating in the serum. Although hormone production is identical in the adrenal and gonad glands, the rate of production and the secreted amount of hormones differ between the sexes and glands.

Figure 1. Illustration of steroid pathway in adrenal and gonad glands.

Concept of Neurosteroids

Several hormones are secreted into the blood from the adrenal and gonad glands. From there, they travel to the brain and spinal cord to perform vital functions involving receptors, synapses, and electrical transmission. These hormones are referred to as “neuro-steroids.” They include pregnenolone, progesterone, estrogen, and testosterone (see Figure 2).

Figure 2. Illustration of path of hormones from bloodstream to brain and spinal cord.

Pregnenolone is extremely plentiful in the brain and performs multiple functions, including regulation of gamma-aminobutyric acid (GABA) and N-methyl-d-aspartate (NMDA) receptors.21-25 Testosterone, estrogen, and progesterone cross the blood–brain barrier and enter the brain. They are involved with multiple receptors and synaptic activities.14-18,26

For example, adequate testosterone levels are required for sufficient opioid binding to receptors and pain relief with opioids.16-18 Adequate cortisol and pregnenolone are also critical for analgesia from administered analgesic.14,15,24,25 These adrenal corticoids help to modulate the blood–brain barrier, opioid effectiveness, and key receptors.14,15,23

Pain Is a Stressor

Fundamental to understanding the relationship between pain and the body’s hormone (endocrine) system is to simply realize that there is no greater stress than pain. Along with such bodily insults as fright, shock, trauma, and surgery, pain causes an activation and stimulation of the hypothalamus–pituitary–adrenal/gonadal system (see Figure 3). The hormone system’s first response to activation by a stressor, including pain, is a release of adrenalin, cortisol, pregnenolone, and possibly other hormones from the adrenal gland. At the time of activation, high levels of these hormones can be detected in the serum, saliva, and urine.

Figure 3. Pain causes the pituitary and adrenal glands to secrete hormones into the blood.

If the pain resolves in a short period of time, serum and other body fluid levels return to normal. If pain persists, hormonal secretions from the adrenal gland will continue in elevated amounts until the pituitary and adrenal glands exhaust their reserve. At this point, serum hormone levels of pregnenolone and cortisol, and possibly others, will show low levels.3 When adequate pain control is administered, abnormal (high or low) serum cortisol and pregnenolone will normalize.3

Severe pain and adrenal exhaustion produce a “vegetative” state (see Table 2). This state, in its severest form, can result in electrolyte depletion, cardiovascular collapse, and death if undiagnosed and untreated. Characteristically, the patient exhibits a blank stare, looks straight ahead, and walks and talks slowly. Blood pressure may be low, but there may be a high pulse rate. Patients have no appetite and may take refuge in bed or on a couch, as movement or any sensory input, including light and sound, enhance their pain. Patients complain of severe fatigue, lethargy, and weakness. Urgent treatment for this state with short-acting opioids and fluids may be required. The most critical laboratory assessment is serum cortisol. If the serum level is low, temporary support with prednisone or methylprednisone is indicated. Serum cortisol levels below 1 mcg/dL have been observed in ambulatory patients referred for treatment.

Table 2. The Vegetative State of Pain-generated Adrenal Exhaustion

Episodic Hypercortisolemia

It is often said that pain ages people. One major, if not the most critical, element in pain’s physiologic insults and progressive deterioration is episodic hypercortisolemia. Even while in opioid treatment, pain that flares or breaks through a medicinal barrier will elevate serum cortisol. Harvey Cushing was a Boston surgeon who, in the late 1800s, identified patients who had a characteristic clinical profile caused by adrenal tumors. Cushing observed hypertension, moon face, posterior cervical bone hypertrophy (“buffalo hump”), truncal obesity, abdominal striae, and muscle wasting of the extremities. Knowledge that this syndrome was caused by excess cortisol in the blood came later as science developed better technology for testing blood. It is the biochemical and tissue-degenerative changes caused by excess cortisol in the blood that are threats to patients with pain.

Last updated on: September 6, 2011
First published on: May 1, 2011