Hormone testing can help determine whether severe pain is overstimulating the endocrine system and which hormones need to be replaced.

A progression of clinical studies over the past four decades provides a sound scientific basis to test and administer specific adrenal and gonadal hormones in patients with chronic pain.1-12 Therefore, I believe that testing and replacement of some hormones are essential elements of pain management. Testing can tell the practitioner whether a treatment regimen is providing adequate pain control, and if not, which hormone replacements are necessary to maximize physical and mental function. This article will review a four-hormone panel screen, which I recommend, as well as a simple replacement guideline (Table 1).

Why Test?

First of all, why test hormone levels in patients with chronic pain? As noted, hormones are essential to the body’s function. When the body becomes stressed, as through injury, the body’s mechanism sets off a chain reaction (flight or fight response) that releases hormones from the hypothalamus, pituitary, and adrenal glands (HPA axis). Initially, the body is flooded with hormones, but if that stress response persists over a long period of time, the body’s organs become depleted of hormones. Because natural pain control and healing is mediated through the endocrine system, if any adrenal or gonadal hormone is deficient, optimal pain control will not be achieved.6,13-15

Essentially all pain is accompanied by inflammation, including neuroinflammation.14,16-20 Pain increases the release of cortisol and pregnenolone, the two major glucocorticoids that control inflammation.16,19,21 Pregnenolone also controls γ-aminobutyric acid (GABA) receptors in the central nervous system (CNS), which regulate pain signals in nerves.21 Adrenal hormones, such as cortisol, are critical for multiple CNS functions including nerve conduction, memory storage, and receptor binding.22-29 Corticotropin-releasing hormone (CRH) is the major pituitary hormone that stimulates production of all adrenal hormones (ie, glucocorticoids), so a deficiency of this hormone can produce profound symptomatology and uncontrolled pain.9,11,30,31 Testosterone is critical for tissue growth including bone.32-34 Pain decreases the amount of testosterone in the body. A deficiency in testosterone actually leads to a catabolic or degenerative state. The four basic mechanisms by which adrenal and gonadal hormones control pain are outlined in Table 2.

Besides identifying which hormones need to be replaced, hormone testing has other merits. First, it will tell you if a severe stress state is present; if so, the clinician may need to institute—or increase dosages of—neuropathic agents, antidepressants, opioids, or other medication used in pain management.12,35,36 Opioids and antidepressants, among the other treatment agents, will not properly bind to CNS receptors if hormone levels are not adequate.7,22Hormones maintain the blood–brain barrier by which hormones and medications flow.8

Another critical reason to conduct hormone testing is to identify a hormone abnormality that may cause long-term complications. This is especially a risk factor when a patient has either too high or too low serum cortisol levels.37-39Many clinical symptoms such as depression, insomnia, hyperalgesia, allodynia, and opioid tolerance and ineffectiveness are often, erroneously, blamed on factors other than the true cause—hormone deficiency. Identification of a hormone deficiency and subsequent hormone replacement may eliminate these symptoms. Simply put, optimal treatment of a chronic pain patient can only be achieved if all adrenal and gonadal hormones are maintained at adequate levels.

Table 3 outlines which pain patients benefit from hormone testing.35,36,40 In my opinion, patients with intractable pain that causes relentless stress to the hypothalamus and pituitary, thus causing the presence of abnormal serum hormone levels, should be tested.40 In all likelihood, patients with constant pain (present 24/7) have centralized their pain. Chronic pain patients who only have intermittent or episodic pain need not be tested.36,40 For example, the average osteoarthritic or neuropathy patient with mild or moderate fluctuating pain on some days or during some hours, but no pain on other days, will not likely show any hormonal abnormality that would require hormone replacement.40

Which Hormones to Test?

Although many hormones can be tested and replaced, the four-hormone screen described here has been deemed the most critical to the evaluation and treatment of a pain patient. All four can be tested on a single early morning blood specimen. These four screens will give you enough information to evaluate the patient’s pain effect on the hormonal system, tell you whether the patient needs more aggressive pain treatment, and identify which hormones must be replaced to prevent complications from hormone abnormalities (Table 4).

A brief description of each of these four hormones is given here. Also, you should know enough about each hormone to educate patients, family, and other concerned parties.

Adrenocorticotropin (ACTH)

The pituitary gland produces ACTH. This hormone is your best, simplest screen as to whether pain is over-stimulating or suppressing hypothalamic and pituitary function. Severe, uncontrolled pain will cause ACTH to rise above normal serum levels.6,13-15 If severe pain goes unabated for a considerable time period, it will depress pituitary function, which results in low serum ACTH levels.

A low serum ACTH level almost always means that pain control has been inadequate for a considerable period of time. An abnormal ACTH, high or low, also likely means that the patient has centralized their pain and is causing excess stimulation of the hypothalamus and pituitary.

Pregnenolone

Pregnenolone is the precursor of all hormones produced in the adrenal and gonad glands (Figure 1). It is also produced in the CNS where it acts as a neurosteroid. The functions of pregnenolone include anti-inflammation, neurogenic growth, and regulation of GABA receptors.1,2,21 In the author’s experience, a low serum pregnenolone level is the most common hormone abnormality observed in patients with uncontrolled pain. When corrected, patients usually report improved pain control, energy, and sleep. Allodynia (pain to light touch) and hyperalgesia (excess pain on pressure), if present, often resolve. Just why serum pregnenolone abnormalities occur is somewhat unclear. High levels may be due to pain’s initial over-stimulation of the pituitary–adrenal–gonadal axis, whereas low levels are most likely due to long-term pain’s depressive effect on the system. In fact, uncontrolled pain suppresses or depletes production of pregnenolone in the CNS.21 Regardless, replacement is most welcome by pain patients as pregnenolone is needed to produce other adrenal-gonadal hormones such as progesterone, estrogen, and dehydroepiandrosterone (DHEA).

Testosterone

This end product of adrenal and gonadal production is now recognized, in males and females, to be critical for pain control, mood, energy, tissue healing, and libido.32-34,41 Most of the publicity about testosterone in pain treatment is related to the fact that opioids exert a preferential suppressive effect on the hypothalamic and pituitary hormones, which produce testosterone.42-45

A key point to be made is that low levels of serum testosterone may occur due to long-standing severe pain in patients who have never been treated with opioids. A major point in pain treatment is that testosterone is an anabolic compound that provides critical tissue growth and healing.

Cortisol

Cortisol is an end product of adrenal metabolism. Normal levels tell the practitioner that pituitary-adrenal homeostasis is at least relatively intact and stable.36 High serum levels mean there is overstimulation of the hypothalamus and pituitary by uncontrolled pain. Low serum levels mean the pain has been so unrelenting that it has suppressed the hormone system. Normal serum levels are critical for pain management. Cortisol is known to be essential for opioid effectiveness in the CNS.7,8 Resolution of inflammation relies on cortisol.16-19 Simply put, any inflammatory condition involving the spine, peripheral nerves, or joints can hardly resolve without adequate cortisol.46-48

Chronic low (Addison’s disease) or high (Cushing’s syndrome) serum cortisol levels have long-term devastating effects.29 Chronic low serum cortisol levels produce a catabolic state with weakness, muscle wasting, depression, weight loss, mental confusion, and lack of desire to physically move or ambulate.41 High chronic cortisol levels produce hypertension, hyperlipidemia, diabetes, upper trunk obesity, and most critically, osteopenia and osteoporosis.37-39 The latter, in chronic pain patients, occurs over time and may not be recognized until there is sudden spine collapse or knee degeneration (see case photographs below).

Additional Hormones for Testing Consideration

A pain practitioner may wish to test other hormones in addition to the four-panel profile recommended here. Additional hormone screens can provide, in some patients, further information. Hormones you may wish to add to the basic panel are listed here, as well as their limitations and benefits to testing and replacement.

DHEA

DHEA is an intermediary compound in the hormone pathway of the adrenals and gonads. It has both precursor and direct functions.42 DHEA is sold over the counter. Serum testing is readily available and laboratories can report low, normal, or high serum concentrations. Occasionally, a low level of DHEA is found in patients on long-term opioids when pregnenolone, cortisol, and testosterone are normal. Replacement dosage is usually 100 to 200 mg per day.

Progesterone and Estrogen

The major limitation to testing for these hormones is that normal levels vary considerably between male and female patients and, in women, vary according to age, menstrual cycles, and menopause status. Laboratories commonly report serum concentrations down to zero, making it difficult to know whether there is a deficiency. Both of these compounds may affect pain levels, so replacement may be in order. As an option to blood testing, short-term clinical trials of either hormone can be done to determine whether a patient may benefit.

Follicle-stimulating and Luteinizing Hormone

Testing for these pituitary hormones is usually done to determine whether opioids are the cause of low testosterone or estrogen levels, as opioids will suppress these sex hormones by suppressing these pituitary hormones.42-45

Free Testosterone and Sex Hormone Binding Globulin (SHBG)

In addition to total testosterone, these measurements may help to determine whether testosterone therapy is needed for libido and sexual function. A total testosterone serum level is one of the basic four-hormone panel because testosterone has many nonsexual functions including affecting energy, depression, tissue growth, and opioid-binding capacity, which are unrelated to libido and sexual function.32,33,41

CRH or Corticotropin-releasing Factor

CRH is produced in the hypothalamus. Investigations have found that pain primarily stimulates or suppresses this hormone, which in turn causes ACTH release.11,13,35 Unfortunately, the lower serum level is usually reported as zero by most laboratories, so a deficiency can be difficult to identify. A high serum level, however, should be interpreted as the presence of centralized pain that is severely out of control.

When to Test?

The time of day should be morning between about 6:00 and 9:00 am. This is because the circadian rhythm of most hormone production in the body hits its peak in early morning. The patient should not fast, but consume their normal food and drink.

The other aspect of “when” relates to follow-up testing. Once hormone abnormalities are detected, quarterly retesting is generally recommended. Monthly, or even more often, follow-up may be needed with emergency replacement of cortisol, pregnenolone, or testosterone. An emergency situation is defined here as a hormone serum level of cortisol, pregnenolone, or testosterone that is near zero.

Guidelines for Management Of New Pain Patients

Each new patient who enters pain treatment and who has constant pain that interferes with activities of daily living such as sleep, eating, dressing, ambulation, socializing, and toiletry should be evaluated by the four-hormone screen. Hormone abnormalities tell the practitioner whether the pain patient is in a severe stress state and requires more aggressive pain management.10,12 On the contrary, a pain patient with a normal hormone profile indicates there is no unusual stress on the pituitary–adrenal–gonadal axis, so not much more, if any, additional pain treatment is required unless the patient demands additional pain relief. Hormone levels should never override a patient’s stated need for additional medication. Here are case examples.

Case Example: More Treatment Needed

A 45-year-old woman developed severe cervical spine degeneration and stenosis following an automobile accident. Her morphine equivalent dose of opioids was about 350 to 400 mg per day. She complained of poor pain control, arm weakness, severe insomnia, fatigue, and a need to be in bed about 4 hours each day. Her early morning serum cortisol concentration was 31.0 mcg/dL (normal is 5 to 20 mcg/dL) and pregnenolone serum concentration was 10 pg/mL (normal above 15 pg/mL). Her morphine daily equivalent dose was raised to 600 mg per day, and she was concomitantly started on a topical analgesic, muscle relaxant, and stretching exercises. Within eight weeks she was no longer bed-bound; slept reasonably well; and claimed much better pain control, energy, and arm movement. A repeat serum cortisol and pregnenolone screen conducted after 12 weeks on a higher opioid dosage showed normal values. In this case, high serum levels of hormones showed that the patient’s pain was not well controlled, indicating a need for increased pain medications.

Case Example: Treatment Regimen Satisfactory

A 50-year-old man with facial neuropathies due to a traumatic injury was referred to my clinic. The patient was taking an oral dose of 10 mg hydrocodone combined with 325 mg acetaminophen 6 to 8 times per day. He also was prescribed zolpidem 10 mg per day and diazepam 10 mg twice per day. The patient stated he had a full-time job and was happy with his pain treatment, but his primary care doctor was uncomfortable with his “high” opioid dosage and referred him for evaluation. The four-hormone panel screen showed normal serum concentrations of ACTH, testosterone, cortisol, and pregnenolone. Other than prescribing some dietary supplements, a topical analgesic, and stretching exercises, no change in his regimen was recommended. Interestingly, insurance companies rarely turn down hormone testing requests, probably because they recognize that serious outcomes can result from abnormal levels.

Guidelines for Patients Already on Opioids

Opioids are now well known to suppress hormone production, and the phrase “opioid endocrinopathy” is often applied to this situation.44,49,50 Clinically, testosterone is the only hormone that is commonly suppressed, and this only occurs in pain patients who have constant pain and take opioids in a dosage of ≥100 mg equivalent of morphine per day. Testosterone suppression is most common with long-acting opioids and around-the-clock dosing.43,44 The hormone system is least suppressed when there are hours in the 24-hour-day cycle in which no opioids are in the blood stream. In addition to testosterone, opioids may occasionally suppress ACTH, cortisol, or pregnenolone in severe pain patients who take high-dose opioids.44,50 In these cases, hormone replacement will be necessary.

A challenge to the practitioner with a severe chronic pain patient who requires high-dose opioids is to know whether the pain, the opioids, or both are causing low serum levels of testosterone and/or other hormones. Sometimes it is difficult to tell but, nevertheless, replacement must be done.

A common clinical mistake is to automatically assume that such symptoms as hyperalgesia, allodynia, depression, insomnia, or poor pain control are caused by opioids when, in reality, hormone deficiencies and/or too low a dose of an opioid (uncontrolled pain causing depletion of stress hormones) may be the culprit. Keep in mind that patients who must take high-dose or long-acting opioids have probably centralized their pain and have ongoing neuroinflammation with progressive tissue destruction, loss of opioid receptors in the CNS, and reorganization of cells (eg, neuroplasticity).46-48 This process causes severe symptoms, and adequate opioid dosages and hormone levels are mandatory to control the neurodestructive process of centralized pain.

The key recommendation is to test for hormone serum levels and replace the hormones that are deficient rather than rely on raising or lowering opioid dosages (Table 5). The finding of high hormone levels means the opioid dosage may be inadequate. However, I do not recommend raising opioid dosages solely on a high-hormone level if a patient states they have good pain relief on their current regimen. If some hormones are high and others low, replace the low ones and adjust the opioid dosage by patient report or attempt some non-opioid measures—but follow-up with additional testing. Low hormone levels, but no high levels, call for replacement and some lowering of opioid dosages, if possible. Here are instructive case illustrations.

Case Example: Elevated Hormone Levels

A 48-year-old woman with severe lumbar spine disease was being treated with a regimen of oxycodone 30 mg four times per day (qid), oxycodone ER 40 mg three times per day, fentanyl lozenges 1,600 mcg qid, carisoprodol 350 mg qid, and an anti-inflammatory agent (ibuprofen 400 mg qid). Her daily morphine equivalent dose ranged from about 350 to 400 mg per day. She claimed to function reasonably well but suffered severe insomnia, and on some days had severe breakthrough pain. Her early morning cortisol level was 32 mcg/dL (normal is 5 to 20 mcg/dL), and ACTH level was 60 g/mL (normal is 6 to 56 g/mL). Adjustments were made to her treatment regimen, including increasing her opioid doses by 10% and adding temazepam 30 mg at bedtime to help with sleep. These adjustments brought her cortisol and corticotropin levels into normal range, and decreased her breakthrough pain and severe insomnia within one month.

Case Example: Cortisol Replacement Needed

The wife of a 51-year-old retired air force officer with severe lumbar spine disease called about her husband. The man has a history of three spinal surgeries and has a documented cytochrome P450 defect, which likely will limit which opioid he can take and/or require a higher-than-normal dosage. The patient’s wife called because her husband had developed a severe pain flare and had suddenly taken to bed, despite a daily morphine equivalent dose of about 700 mg per day, in addition to a regimen of lorazepam (Ativan) 0.5 mg three times per day, celecoxib (Celebrex) 100 mg twice per day, and dextroamphetamine 5 mg twice per day. An early morning serum cortisol concentration was 1.4 mcg/dL (normal is 5 to 20 mcg/dL). He was immediately started on hydrocortisone 20 mg per day to address low cortisol levels and within two days his pain began to return to normal and he was able to leave his bed. No change was made to his opioid dosage. He remained on hydrocortisone for 30 days.

Case Example: Pregnenolone Replacement Needed

A 45-year-old community college instructor weighs 250 pounds and stands 6' 4". He has severe hip dysplasia and lumbar spine degeneration, but he was able to work daily with the use of a fentanyl transdermal patch and oral opioids for breakthrough pain. He has a documented cytochrome P450 defect. His daily morphine equivalent dosage is about 800 mg per day. Without apparent reason, his pain abruptly worsened, and he was unable to walk or work. Simple touch of his painful areas showed hyperalgesia and allodynia. His early morning serum pregnenolone concentration was almost undetectable with a level under 5 pg/mL (normal is more than 15 pg/mL). He was started on 300 mg of chewable sublingual pregnenolone tablets per day, which provided relief within 48 hours. The daily maintenance dosage of pregnenolone was progressively increased over two weeks to 500 mg per day. No change was made to his opioid dosage. He returned to his full-time job and reports he hasn’t missed a workday in three months. He has been maintained on 300 to 400 mg of pregnenolone per day.

Replacement Therapy Guidelines

Pregnenolone, cortisol, and testosterone can be replaced simply. Table 6 gives recommended starting dosages. Pregnenolone and cortisol replacement may not need to be long term, and can usually be stopped when good pain control is achieved. Patients should be retested after 60 to 90 days, and if normal hormone levels are present, attempt to withdraw or lower the hormone dosage. Testosterone replacement is usually only necessary long term in patients whose testosterone level is suppressed by long-acting opioids.42,44 In patients who have hypotestosteronemia due to uncontrolled pain, serum levels usually return to normal with enhanced pain control.

Two adrenal-gonadal hormones that are precursors of other hormones are DHEA and progesterone.51,52 I use DHEA liberally in a dosage of 50 to 100 mg per day and progesterone in topical form. Both are non-prescription and can be purchased over the counter in health food stores. I’ve never had a patient complain of side effects with either agent, and they often seem to aid in the replacement and effectiveness of other hormones.

Can You Hurt Someone By Replacing Hormones?

In a chronic pain patient with constant pain, the value of hormone replacement far outweighs the risks of inadequate hormone levels. Pregnenolone replacement that is too high will produce the nuisance symptoms of headache, dizziness, mental confusion, and acne. These symptoms are well recognized, and when communicated to the patients, the hormone replacement can be stopped or reduced.

The only risk of long-term testosterone replacement is that the serum testosterone levels can rise too high to produce prostate enlargement or cancer of the prostate, breast, or ovary.53 Long before this could happen the androgenic side effects of acne, hirsutism, and hypertension would likely be obvious, particularly in women, at which time the dosage of testosterone could be cut back or testosterone temporarily stopped.

Cortisol serum levels that remain too high for too long can produce Cushing’s syndrome, characterized by hypertension, hyperlipidemia, diabetes, obesity, and osteoporosis.37-39 Adrenal suppression can occur, and it can be permanent. Periodic testing of cortisol and testosterone, which should be done every 60 to 90 days, however, can eliminate these risks. If a serum cortisol level is above normal, simply cut back the dosage. The same applies to pregnenolone and testosterone.

Opioid Dosage Minimization: A Goal of Hormone Treatment

Initiation of opioids or increases in opioid dosage is implemented frequently though, in reality, hormone replacement may obviate the need to do this. For example, in a new patient, a low pregnenolone, cortisol, or testosterone serum level may be preventing a resolution of an inflammatory process.14,16,41 Hormone replacement may obviate the need for starting or increasing opioids. The author sometimes gives an injection of methylprednisolone, testosterone, or estrogen as a challenge test to know whether temporary hormone replacement may be indicated. If the patient gets considerable pain relief within 48 hours, hormone replacement rather than opioids may be possible. This same scenario can be applied to established patients. Before the doses of opioids are increased due to complaints of allodynia, hyperalgesia, depression, or poor pain control, hormones should be tested and replaced.

Summary

Hormone testing and replacement should be a routine procedure in the medical management of intractable, chronic pain. Hormones control inflammation, nerve conduction, tissue growth, and receptor binding—all essential for pain control. It is the “constancy factor” that excessively stimulates or suppresses the hypothalamic–pituitary–adrenal–gonadal system and produces serum hormone abnormalities.

Only those patients who have constant pain and require daily opioid therapy for the management of their pain need to have their hormone levels tested. A basic panel of four hormones is recommended for screening: cortisol, pregnenolone, ACTH, and testosterone. A majority of patients who have hormone abnormalities likely have centralized their pain. When these four hormones are normalized, other adrenal and gonadal hormones will, in the author’s experience, almost always normalize. Long-term hormone replacement may not be needed if good pain control is achieved. Also, a short course of hormones may resolve an inflammatory process and obviate the need for opioids.