Hormone Testing and Replacement in Pain Patients Made Simple
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).
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.
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 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).