Hormone Testing and Replacement: Status Report 2016
Hormone testing and replacement in pain management has progressed in recent years.1 This expansion has been fueled by the availability of hormone profiles, new hormone formulations, and clinical reports that hormone replacement often enhances pain relief, functional abilities, and minimizes opioid administration.2
This paper is a status report on hormone testing and replacement. We hope to give pain practitioners enough information to help them select not only the appropriate tests but also the appropriate chronic pain patients who would benefit from hormone testing and replacement.
Only hormones that have readily available commercial testing and replacement compounds are covered here. For example, the neurohormones, oxytocin, human chorionic gonadotropin, and melatonin may be used in pain management, but, at this time, there is no commercially available test or accepted reference ranges for these hormones. Some pituitary hormones such as adrenocorticotropin (ACTH) and prolactin have accessible commercial testing, but there are no readily available replacement compounds. Consequently, they are only noted here as possible biomarkers of uncontrolled pain. Thyroid testing and treatment in chronic pain patients is somewhat unclear and controversial, so it will be separately covered in a future article.
Physiology of Pain On the Endocrine System
The endocrine system is comprised of multiple organs and glands including the pancreas, brain (thalamus; hypothalamus; pineal: pituitary), thyroid, parathyroid, kidneys, adrenal glands, and the ovaries and testes (Figure 1).
Its principal function is to maintain internal homeostasis by producing hormones essential to the body’s function. Severe pain activates the sympathetic nervous system and has profound physiologic effects on the endocrine system. Multiple hormones act in concert to bring about a biochemical and physiological responses to noxious stimuli.
When the body becomes stressed, as through injury, the body’s mechanism sets off a chain reaction (flight or fight response) whereby the nervous system releases naturally occurring endogenous opioids, including encephalins and endorphins, as well as neurotransmitters and stress hormones, including norepinephrine, epinephrine, and cortisol (glucocorticoid).
Through concerted efforts, these stress hormones and neurotransmitters restore internal homeostasis and turn-off the stress response by a negative feedback inhibition. Patients with chronic pain often display impairment in the hypothalamic–pituitary–adrenal (HPA) axis.
The hypothalamus produces a number of releasing hormones that cause secretion of several pituitary hormones that, in turn, stimulate peripheral target glands: thyroid, adrenals, and gonads (Table 1).
Initially, serum hormone levels from the target glands rise in a biologic effort to eliminate the cause of pain and produce a tissue healing effect.3-7 Current laboratory testing technology easily measures serum elevations of the major adrenal and gonadal hormones including cortisol, pregnenolone, dehydroepiandrosterone (DHEA), estradiol, progesterone, and testosterone.
If severe pain persists, the body’s peripheral glands may exhaust or suppress hormone production, which results in serum levels below their normal range.2,6,8 The first hormone to be depleted is usually pregnenolone or DHEA, precursors of estradiol and testosterone. Some hormones, particularly cortisol, may drop to levels that can produce severe debilitation and in extreme cases, death.9,10
Although frequently overlooked, clinicians should consider testing and subsequent replacement of one or more hormones until the pain crisis is controlled.11
Simply explained, severe chronic pain has a biphasic effect on the endocrine system. Initially it stimulates the system to raise serum hormone levels as a biologic response to stress and injury. The second phase results in low serum levels if severe pain persists and exhausts or fatigues the hypothalamic-pituitary-adrenal-gonadal system. Readers should notice we emphasize severe pain, as mild to moderate pain syndromes, such as is found in osteoarthritis or neuropathic syndromes, may not show serum hormone abnormalities.
Pituitary Hormones as Biomarkers
The anterior pituitary gland secretes hormomes such as growth hormone, thyroid-stimulating hormone (TSH), ACTH, prolactin, leuteinizing hormone (LH), and follicle-stimulating hormone (FSH). The posterior pituitary secretes anti-diuretic hormone and oxytocin.
While these hormones cannot be replaced by exogenous administration, pituitary serum hormone levels may represent biomarkers of uncontrolled pain12 or suppression from pain treatment (ie, opioid-induced suppression). As with peripheral target organ serum hormone levels, the effect of uncontrolled severe pain on pituitary hormones is biphasic: in the initial phase, serum pituitary hormone levels will rise, but over time, will drop below normal range if severe pain goes unabated.
Certain hormones have physiologic effects that are critical for pain relief, neuroprotection, and neurogenesis. It is not well appreciated, for example, that some hormones help maintain the blood-brain barrier, enhance central nervous system (CNS) receptor activity, and control neural transmission.13-18 Other hormones suppress neuroinflammation and promote neurogenesis.19-24
For example, adult neurogenesis has been linked to hippocampal function,25 including learning and memory, anxiety regulation, and feedback of the stress response. It is not surprising that stress, which affects hippocampal function, also alters the production and survival of new neurons.
Glucocorticoids, along with other neurochemicals (including thyroid hormone),26 have been implicated in stress-induced impairment of adult neurogenesis. Paradoxically, increases in corticosterone levels are sometimes associated with enhanced adult neurogenesis in the hippocampus.25 The discovery of agents that buffer against the suppressive influence of elevated glucocorticoids may provide clues to reversing pathological processes like pain that arise from chronic exposure to physiological stress.
Opioid Suppression of Hormone Production
In addition to exhaustion of the endocrine system by underlying disease processes, some serum hormone levels may become depressed due to opioid and other drug administration, as well as from severe, persistent pain.27-31 The endocrine systems of both men and women can be affected by opioids.
For example, it has long been known that sepsis or other systemic disease may interfere with thyroid metabolism. This condition has been labeled “euthyroid sick syndrome.” Other examples are painful autoimmune disorders that may affect pituitary and adrenal production. Traumatic brain injury, for example, may cause multiple pituitary insufficiencies.