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8 Articles in Volume 16, Issue #3
CDC Issues Final Guidelines for Opioid Prescribing: PPM Editorial Board Responds
Don't Flinch From Prescribing Pain Medications!
Help Patients Achieve Diet/Weight Goals to Manage Pain
Hormone Testing and Replacement: Status Report 2016
Living With, and Managing, Chronic Pain: A Patient’s Story
Nerve Decompression Surgery Can Reverse Neuropathy of the Foot
Pulsed Electromagnetic Field Therapy: Innovative Treatment for Diabetic Neuropathy
Specialized Pharmacies Step Into Risk-Management Role

Hormone Testing and Replacement: Status Report 2016

Hormones play a critical role in pain care as they promote analgesia, neuroprotection, healing, and neurogenesis.

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.

The adrenal gland sits atop the kidneys. Patients with chronic pain often display impairment in the hypothalamic-pituitary-adrenal axis.

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.

Physiologic Attributes

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.

Although any opioid administration may depress testosterone and other hormone levels, long-acting and intrathecal opioids are more likely to cause hypothalamic and pituitary hormone suppression.30-34 For unknown reasons, opioids preferentially suppress the gonadotropins, LH, and FSH hormones. They will sometimes suppress ACTH and uncommonly suppress TSH. Serum hormone levels of testosterone, estradiol, progesterone, cortisol, DHEA, and pregnenolone may individually or collectively be low in the serum of patients who take opioids and require replacement.

Although not well documented, low hormone levels related to opioids, in the authors opinion, often result in hyperalgesia and/or an ineffective response to known analgesics.22 The symptoms of hypotestosteronemia and other opioid-suppressed hormones are now well documented (Table 2).28 We call attention to chronic pain patients who are on opioids and develop profound weakness, lethargy, fatigue, and depression as it may be caused by extremely low serum cortisol, DHEA, or testosterone. These patients usually benefits from replacement.10,27-35

Hormones That Can Be Replaced

There are some key hormones that are critical for maximal pain care including analgesia, neuroprotection, and healing. Thanks to accessible hormone profile testing and available replacement hormones, practitioners can now obtain serum hormone levels and replace or supplement when necessary (Table 3).

Laboratory testing to assess for the presence of endocrine disorders is complex and may include total testosterone, free testosterone, sex hormone binding globulin (SHBG), LH, FSH, DHEAS, and estradiol, and may require more specific evaluation of adrenal function.36 As there are no formal guidelines available, it is the opinion of the authors that testing should be individualized based on patient signs and symptoms, with a consultation with an endocrinologist or other specialist when necessary.

Testosterone levels peak in men at about age 20, and then slowly decline. When testing for testosterone, it is important to remember that levels are highest in the mornings, especially in younger patients. In addition, testosterone levels can fluctuate substantially day-to-day, and androgen status should be based on more than a single measurement.37 Although not specific to chronic pain patients, in 2013, the Endocrine Society Task Force published a guideline for Testosterone Therapy in Men with Androgen Deficiency Syndromes, which recommended best-practices for assessment, treatment, and ongoing monitoring.38

Women with hypopituitarism and secondary hypogonadism have been found to have reduced levels of total testosterone, free testosterone, androstenedione, and DHEAS levels as compared to healthy controls.39,40 While women receiving chronic opioid therapy may develop similar symptoms related to testosterone deficiency as men, there are even fewer studies and no guidelines for the assessment and treatment of opioid-related androgen deficiency in women. Therefore, the measurements of bone density, estradiol, and free testosterone may guide appropriate therapy.41

When treating hormone deficiencies, such as cortisol, DHEA, estradiol, pregnenolone, progesterone, and testosterone, we recommend that the starting dosages be low and titrated upward over 6 to 8 weeks as long as the patient does not show side effects. Serum levels should be retested after this time period. Although synthetic analogues, such as prednisone or  medroxyprogesterone, may be required to relieve severe symptoms of pain, fatigue, and depression, the use of bioidentical hormones may provide an optimal safety profile.

Similar to safety actions taken regarding NSAIDs, the US Food and Drug Administration (FDA) has commented on bioidentical hormone replacement therapy (BHRT), stating that because of “uncertainties surrounding their safety and effectiveness, the FDA suggests the use of the bioidentical agents at the lowest effective dose for the shortest time needed.”42

Hormone Therapy

Hormone replacement is somewhat of a misnomer. In pain management, we normally deal with a normal gland that doesn’t require replacement but “sub-replacement.” For example, the adrenals produce about 30 mg of cortisol a day, but in pain patients with sub-optimal cortisol levels, only 10 to 15 mg of cortisol will usually need to be replaced. Also, the sub-replacement dosage may not be required long-term.

We recommend that sub-replacement hormones be reduced or stopped once normal serum levels are achieved and the patient’s pain is reasonably under control. Once the pain crisis subsides, patients can often stop their hormones and maintain normal serum levels. However, other patients with ongoing chronic pain may need long-term hormone administration.

Formulations and Analogues

Most hormone supplements shown in Table 3 can be ingested orally with the exception of testosterone, which has very poor oral bioavailability. Consequently, it is administered in topical, transmucosal, injection, or pellet formulations (including implanted pellets). Sublingual, topical, and pellet preparations can be compounded to meet a patient’s individual needs. Injections of testosterone and estradiol are available and may be the treatment of choice due to clinical efficacy and cost consideration. Estradiol is also now available in implanted pellets.

Synthetic analogues of cortisol, estradiol, and progesterone may be more effective in some patients, although they may pose additional risks. At this time, we do not recommend one formulation or analogue over another. Practitioners should explore their resources and select the best option for their individual practice and patients.

Summary

Good pain management includes not only an expert knowledge of analgesic drugs, but an understanding of the physiological effects of pain on the endocrine system. If unrelieved, pain can activate the catabolic stress response process, and when prolonged, can contribute to endocrine abnormalities that are often overlooked. Hormones are critical for pain care in that they promote analgesia, neuroprotection, healing, and neurogenesis. In recent years, commercial laboratories have developed hormone profiles that make it convenient for the pain practitioner to assess the endocrine status of a pain patient.

Pain practitioners are encouraged to investigate the logistics of hormone testing and hormone replacement, on either a short- or long-term basis, as it may be of benefit to our chronic pain patients who seem refractory to conventional analgesic therapies.

Last updated on: June 21, 2017
Continue Reading:
Living With, and Managing, Chronic Pain: A Patient’s Story

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