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.

By Forest Tennant, MD, DPH

Page 1 of 4

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

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.

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).

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.

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.

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.

By Forest Tennant, MD, DPH

Page 2 of 4

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.
Included here are hyperglycemia, hyperlipidemia, immune suppression, osteoporosis, and brain atrophy, all of which are commonly observed in patients with severe, chronic pain (see Figure 4). There is no greater treatment need in patients with severe, chronic pain than to control pain flares, because any severe pain will raise cortisol levels. It is highly recommended that all patients with severe, chronic pain be initially screened with an early-morning cortisol level and that patients be periodically monitored with serum cortisol levels, especially if they exhibit poor pain control or develop hypertension, hyperglycemia, hyperlipidemia, osteoporosis, or mental difficulties.

Here are two illustrative cases:
A 35-year-old woman had severe facial neuropathies sustained in a beating. Her initial cortisol level was 58 mcg/dL (normal is 5 to 20 mcg/dL). Within 10 years, despite medical pain treatment, her thoracic spine collapsed from osteoporosis, and she required multiple surgeries with implanted metal rods.
A 25-year-old woman with severe fibromyalgia presented with a serum cortisol of 28 mcg/dL. Despite medical treatment, she developed mental incapacity and required custodial care within 10 years.

Screening and Monitoring

The easiest way to identify hormone abnormalities and provide hormonal therapy is to routinely screen patients with pain who need around-the-clock, daily opioid medication. I recommend a 3-hormone screen: pregnenolone, cortisol, and testosterone (see Table 3). A simple, early-morning fasting blood specimen is all that is required, and all commercial laboratories can provide the screen. In patients who require daily, around-the-clock opioids, this screen should be repeated every 3 to 6 months so that the need for replacement hormones can be identified.

Essentially, all health plans will pay for these 3 hormones, as they are relatively inexpensive and easy to assay. More important, these 3 hormones have well-published normal ranges and provide a good picture of pituitary, adrenal, and gonadal function as well as which hormones need to be replaced.

Biological Indicator of Pain

There has been interest in the use of biological tests as an objective indicator that pain is present for a long time. Serum or saliva levels of cortisol and pregnenolone are excellent indicators of uncontrolled pain. High levels of these hormones indicate severe pain and a good adrenal reserve. Low levels indicate severe pain with exhaustion of pituitary or adrenal reserves. If testosterone serum levels are low and the patient is not on opioid drugs, this finding is suggestive of pituitary exhaustion. The author has identified a small number of patients with severe, uncontrolled, intractable pain who demonstrated a number of pituitary deficiencies that resolved with adequate pain treatment. Today, most patients with pain fortunately are able to receive sufficient pain treatment to avoid pituitary exhaustion, so it is unknown how often this occurs.

Opioid Pituitary Suppression

As discussed above, severe pain per se has a profound impact on the body’s hormonal system. Unfortunately, the administration of daily opioids may cause suppression of some pituitary hormones, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This suppression likely is related to the presence of opioid receptors in the hypothalamus. Recently, the term “opioid endocrinopathy” has been applied to this condition. The most common hormones suppressed by opioids are pregnenolone and testosterone, which results from low serum LH or FSH. Suppression occurs approximately equally in men and women. Other hormones, including cortisol and thyroid, are rarely suppressed.

Clinical Manifestations of Testosterone Deficiency

Testosterone deficiency is clinically quite apparent in patients with pain maintained on opioids (see Table 4). Patients complain of fatigue, weight gain, depression, and loss of libido, similar to the complaints of patients without pain who have testosterone deficiencies. They also complain of poor pain control and routinely ask for higher opioid dosages. When higher doses of opioids are given, however, pain relief may not be forthcoming, as adequate testosterone levels are required for central opioid receptor binding. These patients therefore may be misdiagnosed as having hyperalgesia. In addition, sleep patterns, which are routinely disturbed in patients with pain, may worsen, as adequate testosterone levels are required for normal sleep.

Laboratory Screening for Testosterone

When testosterone deficiency is suspected, a one-time blood specimen is adequate to make the diagnosis in a patient with pain maintained on opioids. Either a low total or free testosterone level should be considered confirmatory. For the treatment of testosterone deficiency, clinicians can prescribe either human chorionic gonadotropin (HCG) or a testosterone formulation. It is poorly appreciated that the labeled indication of HCG is hypogonadism. It is discussed more fully below.

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.

By Forest Tennant, MD, DPH

Page 3 of 4

There are multiple testosterone formulations, including topical, injection, sublingual, and patch preparations. All are labeled only for male use. Administration to women is not approved by the FDA, so female patients need to be informed of this. When testosterone is deficient in women with pain, it must be replaced, otherwise they will not obtain adequate pain relief.¹¹ I recommend the starting dose in women to be one fourth to one half of that in men. The initial dosage can be titrated upward as needed based on symptoms.
The major complications observed with testosterone or HCG are acne, facial hair, and/or loss of scalp hair in women. Testosterone dosage must, of course, be reduced if these occur.
The following case illustrates typical laboratory findings in patients with pain with opioid-induced suppression of hormones and need for testosterone and pregnenolone replacement. Note that cortisol level is normal. It is unknown why opioids preferentially suppress the gonadal rather than the adrenal or thyroid hormones.
A 39-year-old former veteran who weighed 292 pounds had severe arthritis of his knees and spine. He required daily methadone, oxycodone, and hydrocodone for pain control. He complained of poor pain relief, impotence, low libido, fatigue, insomnia, and depression. Laboratory screening showed low pregnenolone levels of less than 5 ng/dL (normal is 13-208), low total testosterone of 141 ng/dL (normal is 250-1,000), and normal cortisol of 9.5 mcg/dL. He was prescribed pregnenolone 400 mg per day and topical testosterone. Within 1 month, the patient reported greater pain control, more energy, better sleep, and a return to normal sexual activity.
The following case demonstrates the usual finding in a patient with pain in which the LH and FSH are suppressed by opioids, but the adrenocorticotropic hormone (ACTH) or thyroid-stimulating hormone (TSH) are not.
A 30-year-old man had Lyme-induced arthritis and fibromyalgia. His opioid treatment consisted of transdermal fentanyl with oxycodone, and hydromorphone for breakthrough pain. He complained of impotence, insomnia, lethargy, and poor pain control. Serum testing revealed a low testosterone concentration of 59 ng/dL. His FSH and LH were below normal, but his serum cortisol, ACTH, and TSH were normal.

Pregnenolone Deficiency

Pregnenolone is not a well-known hormone, but it is critical for adequate pain control and many mental functions.^21-25 Patients with pregnenolone deficiency tend to complain of anxiety, poor mental concentration, and inadequate pain control, probably related to pregnenolone’s effects on GABA and NMDA receptors.^24,25 Replacement dosage is extremely variable and ranges from 50 to 800 mg per day.

Progesterone

This hormone is the newest to find its way into pain treatment. General knowledge suggests that progesterone is a female hormone that helps to regulate the menstrual cycle and maintain pregnancy. We now know that progesterone has critical anabolic and immunologic functions in women and men. Progesterone levels may decrease in chronic pain. A recent study of US soldiers in Iraq showed that a metabolite of progesterone, allopregnanolone, was lowered in soldiers with pain.²⁶ This study suggests that progesterone is required for pain control and that supplementation with progesterone may be beneficial. To this end, the author has begun trials with low-dose oral and topical progesterone, as the agent is rapidly absorbed through the skin. Early results are highly encouraging. A glance at Figure 1 shows that progesterone is a precursor of cortisol, estrogen, and testosterone. Few side effects have been reported with progesterone.
The following case illustrates that progesterone administration requires further investigation.
A 52-year-old man sustained a back injury 24 years prior that required multiple surgeries, vertebral fusion, and implanted metal rods. In his twenty-second year on opioids, he was maintained on 100 mcg daily of transdermal fentanyl, 9,600 mcg daily of transmucosal fentanyl, and 60 mg daily of oxycodone. He had a testosterone deficiency of 154 ng/dL, and was taking a systemic testosterone replacement. He was given a topical soluble cream preparation of medroxyprogesterone 10 mg per ounce to apply over his pain site. He received good relief with topical progesterone, so he was prescribed oral medroxyprogesterone at 10 mg twice daily. Within 1 month, he reported a dramatic reduction in pain and reduction in his opioid dosage by 50% and halted his systemic testosterone replacement, claiming that medroxyprogesterone gave him more libido and ability to engage in sexual activity than testosterone. He has maintained his reduced pain, lower opioid dosage, and increased libido for 6 months.

Human Chorionic Gonadotropin

The author first became aware of the potential pain-reducing effect of HCG when a weight reduction clinic noted that its obese patients with fibromyalgia and osteoarthritis had reduced pain when HCG was prescribed for weight loss. The dosage of HCG used was about 10 to 30 units 1 to 3 times per week. Personal interviews with some of these patients convinced the author that HCG should be investigated as a possible adjunct for pain treatment.
HCG is a poorly understood hormone. It isn’t just a compound secreted in pregnant women to maintain placenta and produce a positive pregnancy test. It is constantly secreted by the pituitary in women and men, as it has major hormone stimulation and androgenic effects.^28,29 The HCG molecule is composed of two amino acid subunits. One is identical to FSH, LH, and TSH. The other is an androgenic unit that activates cyclic adenosine monophosphate (c-AMP) and produces nitric oxide, which is known to increase blood flow.
The hormone-stimulating component accounts for its labeled indication for hypogonadism. The adrogenic component accounts for its use in athletes and bodybuilders, who apparently take it to build bigger blood vessels on their upper torso. Athletes who episodically use (cycle) anabolic steroids like to use HCG when they stop steroids and want to revive their own testosterone and libido.

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.

By Forest Tennant, MD, DPH

Page 4 of 4

To date, the author and colleagues have given HCG to about 30 patients with intractable pain who are maintained on opioids. One group of 8 has taken it for more than a year. The others have used it in various dosages for various lengths of time. Our dosages have been 500 to 1,000 units subcutaneously or 250 to 500 units as a sublingual liquid, 1 to 3 times per week. The only side effect has been acne in one woman.
To date, clinical results reflect, we believe, HCG’s two base mechanisms: gonadal and thyroid stimulation; and anabolic regeneration. Almost all patients report, as with testosterone and progesterone, increased energy, pain control, and libido. Almost all patients have reduced opioid dosages and improved sleep.

Can HCG and Other Hormones Produce Neuronal Regeneration?

Our early experience with HCG, pregnenolone, progesterone, and testosterone suggests that these hormones may directly or indirectly produce regeneration of neural tissue. The anecdotal clinical evidence is less pain, lowered opioid dosages, less insomnia, and elevated libido. Studies of the past two decades clearly show that severe pain may cause reorganization (neuroplasticity) of neurons and glial cells as well as loss of brain tissue. Intermittent, excess cortisol in the blood is a known cause of central brain tissue loss.^20,27 We clinically need to find hormones to ameliorate the neural changes that pain may cause. HCG appears to be a relatively harmless and inexpensive approach that can be easily adopted by any pain practitioner. Other hormones, such as pregnenolone, progesterone, or testosterone, may prove to be better agents or agents that can be simultaneously administered with HCG.

Summary

Pain is a stressor, just as fright, shock, trauma, and surgery are. When pain begins, the pituitary and adrenal glands attempt to provide a healing, immune response by secreting extra cortisol, pregnenolone, adrenalin, and other hormones into the general blood circulation. If severe pain goes uncontrolled, the adrenal glands may become exhausted, resulting in low serum levels of pregnenolone and cortisol. Although adequate pain control will usually normalize or balance serum hormone levels, supplementation may have to be given. Daily opioid administration frequently causes suppression of testosterone and pregnenolone, which can simply and easily be replaced. Some adrenal and gonadal hormones are secreted into the bloodstream and travel to the brain and spinal cord, where they have profound effects on pain control, mood, sleep, and mental capacity. The term “neurosteroid” is frequently applied to these compounds, which include pregnenolone, estrogen, progesterone, and testosterone. If any of these hormones is deficient, pain control is impaired, and the patient will complain of such symptoms as insomnia, ineffective medication, depression, fatigue, allodynia, and hyperalgesia.
A profound result of recurrent, episodic pain flares is that excess cortisol enters the blood to give a “pseudo” Cushing’s syndrome. Serious side effects may result, including hypertension, hyperlipidemia, diabetes, osteoporosis, and brain tissue atrophy with loss of mental and intellectual powers. Patients with severe, chronic pain should therefore be periodically screened for cortisol excess and deficiencies. HCG is an intriguing compound that contains FSH, LH, and TSH. It also has an anabolic, tissue-building component. HCG’s labeled indication is hypogonadism, and its early clinical use indicates that it may have considerable merit as an adjunct to pain treatment. It may neutralize opioid suppression of testosterone as well as produce its own anabolic growth effects on nerve tissue.