Neurohormones in Pain and Headache Management: New and Emerging Concepts
The recent discovery and awareness that the central nervous system (CNS) makes specific hormones for intrinsic use in addition to those for peripheral use is a profound finding that is critical to clinical pain and headache management. Some neurohormones provide the physiologic effects of neuroprotection and neurogenesis that are essential for pain reduction, prevention, and treatment.
Following is an attempt to provide an early status report on what we do (and don’t) know about the function of neurohormones relative to pain management. Be clearly advised that this report is elementary and, undoubtedly, will be subject to expansion and revision as more basic science and clinical experience are accumulated. This review looks at 8 neurohormones that are in early clinical use.
Definition of Neurohormones
The CNS, including the pituitary gland, produces numerous hormones, but relatively few are known to have pain-related functions within the CNS.1-22 For the purposes of this article, we define a neurohormone as a hormone that is produced, retained, and has functions within the CNS that promote pain control. Additional hormones surely will be found.
Table 1 lists the 8 neurohormones that have been identified as affecting pain. Five of these are called neurosteroids because they have the steroid moiety (4 carbon rings) as part of their chemical structure.9-10 These are dehydroepiandrosterone (DHEA), estradiol, pregnenolone, progesterone, and testosterone. The 3 remaining neurohormones are human chorionic gonadotropin (HCG), human growth hormone (HGH), and oxytocin.
We did not include hormones that are produced in the peripheral endocrine system and then transported by arterial blood into the CNS for biologic actions, such as cortisol, epinephrine, thyroid hormones, or insulin.11-13 Also excluded from discussion are endorphins, prolactin, melatonin, vitamins (ie, D2 and D3), dopamine, cytokines, and various releasing hormones because, although they may have a pain modulatory function, they are generally considered neurotransmitters or neuromodulators. At this time, many of these hormones cannot be readily measured in serum or formulated into compounds.
Neurohormones appear to have 3 basic pain control functions: analgesia or pain modulation; neuroprotection of CNS cells; and neurogenesis, defined as re-growth of damaged tissue.14-21 Table 2 outlines the biologic actions of neurohormones. Neurohormones likely exert some neuromodulatory and transmission effects, and some appear to have direct analgesic properties. For example, oxytocin is known to surge during childbirth as a component of natural anesthesia.
Serum Testing: Why, When, and How
One of the best uses of hormone profiles is for chronic pain patients who have not responded to a standard treatment regimen and continue to have uncontrolled pain.22 A hormone profile can measure all 5 neurosteroids; HCG, HGH, and oxytocin testing usually are only available through specialty labs that use early-phase testing protocols with non-standard assays.
A serum concentration of a hormone, such as pregnenolone, progesterone, or DHEA, has adrenal and gonadal sources, as well as CNS sources. Thus, it is unknown how much of a serum neurohormone concentration is from CNS versus peripheral sources. However, pain control requires hormone homeostasis in both the CNS and periphery, so a low serum level can be treated without concern as to which sources are not producing enough. Results from a hormone profile will give the practitioner some clues as to why a treatment regimen is not effective and provide enough information so the clinician can take measures to help the patient adjust, or modify, his or her regimen to attain better pain control.22 For example, serum testing is recommended before starting DHEA, pregnenolone, progesterone, testosterone, and estradiol.
Our recommendation is that hormone administration be restricted to patients who show serum deficiencies. A goal of hormone administration should be to bring serum concentrations into the normal or optimal range.
Progesterone and Allopregnanolone
Although a great deal of basic science and animal research has been conducted on neurohormones,23-53 prior to 2010 there was little interest in neurohormones other than testosterone for pain management. In 2010, Kilts et al observed that nearly half of veterans returning from the Middle East who experienced persistent pain had low serum levels of allopregnanolone,23 a metabolite of progesterone.25,29,43 It was theorized that the pain experienced by the veterans was due to a lack of progesterone, which has been shown in multiple studies to reduce neuroinflammation, oxidative stress, and brain damage in animals.24,27,33,39 Progesterone also may be a precursor of cortisol, the central hormone in the stress response.
Progesterone is being studied in cerebral vascular accidents and traumatic brain injury (TBI).39-42 Our preliminary open-label investigation of progesterone is encouraging, but no specific recommendations on its clinical use can be made yet.27 However, it is important to take a broader look at the pain patient’s hormonal status and measure it, even in young men and women. Progesterone cannot be considered ONLY the “baby” hormone anymore!
DHEA is, on a quantitative basis, the most plentiful hormone in the human body. It circulates in abundance in the form of a sulfated reserve (DHEA-S).54-73 DHEA, the levels of which decline with age,59 has been well studied and used as a dietary and hormonal supplement for hyperlipidemia and cardiovascular disorders.68-73 It also has been a favorite anti-aging and stress-relieving dietary supplement.
Enthusiasm for use of DHEA in pain management began in 1994, when it was found to suppress pain and pain flares in patients with systemic lupus erythematosus (SLE).68 Since that time, a number of studies have confirmed its effectiveness in SLE. It clearly possesses anti-inflammatory properties and suppresses interleukin 10 synthesis in women with SLE.
In addition to having peripheral anti-inflammatory actions, DHEA also has been shown to be produced in the CNS and have additional critical properties related to pain management.56 It is neuroprotective and inhibits tumor necrosis factor alpha (TNF-a) and CNS inflammatory markers by inhibiting production of monocytes, astrocytes, and microglial cells. Its neuroprotective action in the CNS is at least partially attributed to conversion to estrogen and estradiol.54