Testosterone Replacement in Chronic Pain Patients

Adequate testosterone serum levels are required in males and females not just for libido and sexual function but also for cellular growth, healing, maintenance of muscle mass and bone, and central nervous system maintenance of opioid receptors, blood- brain barrier, and dopamine-norepinephrine activity.
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Testosterone deficiency in chronic pain patients has now been recognized by many observers.1-6 Due to its critical biologic functions in pain control, testosterone testing and replacement (TR) should now become a mandatory component in the treatment of chronic pain. This paper summarizes the physiologic actions of testosterone relative to pain management and lays out practical guidelines for testing and treatment that can easily be adapted to pain practice.

Why the Necessity of Testosterone?

Unfortunately, the mention of the word “testosterone” usually calls to mind a misconception that it is simply the hormone needed for male libido and erectile function. This biologic function is only one of many of testosterone’s critical functions (see Table 1). Furthermore, adequate biologic testosterone levels are as critically equal to the female as male chronic pain patient.3,7 First, adequate testosterone levels are needed for satisfactory pain control as this hormone is intricately involved in endogenous opioid activity.8-10 Testosterone is also necessary for opioid receptor binding, maintenance of blood-brain barrier transport, and activation of dopamine and norepinephrine activity.11,12 Consequently, a lack of testosterone activity in the CNS may result in poor pain control, depression, sleep disturbances, and lack of energy and motivation. In the periphery, testosterone functions as a primary androgenic compound for tissue healing.7 Adequate testosterone levels have long been known to be necessary for muscle maintenance, exercise tolerance, and prevention of osteoporosis. Compression fractures are known to occur in men and women who have testosterone deficiency.6 A deficiency of testosterone, therefore, impairs healing and control of inflammation at pain sites.

Table 1. Testosterone Functions in Chronic Pain Patients
  • Opioid receptor binding
  • Dopamine-norepinephrine activity
  • Maintenance of blood-brain barrier
  • Androgenic-healing/tissue growth
  • Libido
  • Erectile activity (males)
  • Maintenance of muscle and bone mass
  • Exercise tolerance

Another great misconception is that testosterone is purely a male hormone. Even in the female, an adequate testosterone serum level is necessary for libido. Further, all of testosterone’s CNS and androgenic-immunologic functions apply equally to females. The only difference and consideration with TR in females is that females carry a lower serum concentration and a lower dosage is usually required for replacement.

Physiologic Production

The hypothalamus produces gonado-tropin releasing hormone (GnRH) which causes the pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH assist in testosterone production by the adrenal and gonads. Although testosterone was previously thought to be only produced in the testicles, it is now clear that it can be produced in the adrenal and ovary (see Figure 1). Of considerable importance is the fact that testosterone converts to estradiol and dihydrotestosterone in peripheral tissue. Estrogens are known to have a potent affect on depression by virtue of activity in the CNS as well as on bone formation. Although our understanding is elementary, it appears certain that severe, uncontrolled pain causes anatomic changes in the CNS by virtue of neuroplasticity. Hormonal therapy is emerging as critical to adequately treat an altered CNS that develops in response to severe chronic pain.

Figure 1. Pathway of Testosterone Formation and Conversion in Peripheral Tissue. (Adapted from Williams Textbook of Endocrinology, 10th edition, Saunders, Philadelphia. 2003. p713.)

Mechanism of Testosterone Depletion

There may be two reasons for testosterone depletion in a chronic pain patient (see Table 2). One is pituitary insufficiency caused by severe pain, per se. Constant, persistent, uncontrolled pain will, over time, exert enough stress on the hypothalamus and pituitary (GnRH, LH, FSH) to cause the inadequate secretion of testosterone from the adrenal and gonads. When the cause of hypotestosteronemia is hypothalamic-pituitary insufficiency, other hormones such as cortisol, pregnenolone, or thyroid may likely show serum deficiencies. The second and most common cause of testosterone deficiency is opioid administration.1-2 Low testosterone levels have been observed with essentially all oral and intrathecal opioids.2,5 Low testosterone serum levels are primarily caused by opioid suppression of GnRH in the hypothalamus. Opioids may also directly impair testosterone production in the adrenal or gonads. Both causes of hypotestosteronemia may simultaneously exist. Also, both cases require testosterone replacement. It is unknown if testosterone suppression by opioids is opioid-specific, dose-related, or related to opioid serum levels.

Table 2. Two Causes of Hypotestosteronemia
  1. Pituitary deficiency caused by over- stress of uncontrolled chronic pain
  2. Opioid administration

Testing For Testosterone Deficiency

Simply order a morning serum testosterone level. Laboratories now report a patient’s serum concentration as well as normal ranges for males and females. Units of measure may vary between laboratories. The total serum testosterone concentration has protein-bound and unbound components.13-15 The free, bioavailable, or unbound component is generally believed to be the fraction most involved with libido and sexual function. We believe, however, that the total serum testosterone levels may be a more critical evaluation for pain management purposes, since protein-bound testosterone may be necessary to either enter some body compartments such as in the CNS, spinal cord, or pain site to perform its necessary functions. Consequently, pain practitioners should consider low levels of either total serum testosterone or free unbound testosterone to indicate a deficiency that requires replacement.

Who Should Be Tested

If financial resources are available, all chronic pain patients who require opioid administration, including those patients who are currently taking opioids, should be screened. Those patients currently in opioid treatment and who complain of lethargy, inadequate pain control, depression, weakness, and lack of libido, are obvious candidates for serum testing (see Tables 3 and 4).

First published on: July 1, 2010