The Physiologic Effects of Pain on Hormones

The Physiologic Effects of Pain on the Endocrine System – Pain Ther. – by Forest Tennant – 2013 Dec – free full-text PMC article

Severe pain has profound physiologic effects on the endocrine system.

Serum hormone abnormalities may result and these serve as biomarkers for the presence of severe pain and the need to replace hormones to achieve pain control.

Initially, severe pain causes a hyperarousal of the hypothalamic–pituitary–adrenal system which results in elevated serum hormone levels such as adrenocorticotropin, cortisol, and pregnenolone. 

If the severe pain does not abate, however, the system cannot maintain its normal hormone production and serum levels of some hormones may drop below normal range. 

Some hormones are so critical to pain control that a deficiency may enhance pain and retard healing.


Fundamentally, severe pain, whether it be acute or chronic, is a severe stressor that activates the hypothalamic–pituitary–adrenal–thyroid–gonadal (HPATG) system, which is the major stress control mechanism of the body.

This system is often referred to as an ‘axis’ since it is a closed system with hormonal feedback or controls within the system

The biologic purpose of this system (see Fig. 1) is to produce additional hormones in the thyroid, adrenals, and gonads, and secrete them into the serum as these compounds are required by the body for many pain-control functions, including protection and regeneration of injured tissue, immunologic activity, and metabolic controls.

Figure 1: Pain stimulation of the hormone system causes adrenal, gonad and thyroid hormone levels to elevate in the serum.

Once these extra hormones, such as thyroid, cortisol, or testosterone, enter the serum, they travel throughout the body to target areas, including injured nerves and the central nervous system (CNS)

Although it is known that pain has an effect on

  • neurohormones produced in the brain,
  • insulin produced in the pancreas, and
  • adrenalin produced in the adrenal medulla,

there are few studies or reports on these effects

Over the past 50 years, however, there have been numerous reports and studies on pain’s physiologic effect on the HPATG system, so this is the focus of this paper

It is also cogent to note that the accumulated information and understanding about the effects of pain on the HPATG system is now such that testing and replacement of certain hormones should be a basic foundation of clinical pain treatment.

Hormone Functions in Pain Control

Adequate pain control may not be achieved without homeostasis of certain hormones

The critical pain-control hormones that are produced in glands outside the CNS are

  • cortisol,
  • pregnenolone,
  • dehydroepiandrosterone (DHEA),
  • progesterone,
  • testosterone,
  • estrogen, and
  • thyroid.

Among the primary pain-control functions of these hormones are

  • immune and anti-inflammatory actions,
  • cellular protection,
  • tissue regeneration,
  • glucose control, and
  • modulation of CNS receptors, the blood–brain barrier, and nerve conduction.

Given the CNS effects of certain hormones, analgesics such as anti-depressants, neuropathic agents and opioids, may not achieve maximal analgesic responses without hormone homeostasis.

The Releasing Hormones

Pain signals that reach the brain from any injury in the peripheral nervous system activate three releasing hormones in the hypothalamus

These are

  • corticotropin releasing hormone (CRH),
  • gonadal releasing hormone (GRH), and
  • thyroid releasing hormone (TRH)

These three hormones, in turn, cause the anterior pituitary to release into serum

  • adrenal corticotropin hormone (ACTH),
  • follicle stimulating hormone (FSH),
  • luteinizing hormone (LH), and
  • thyroid stimulating hormone (TSH).

The end organs for stimulation are the

  • adrenals,
  • gonads, and
  • thyroid, 

which release into the serum hormones necessary for pain control including

  • cortisol,
  • pregnenolone,
  • DHEA,
  • testosterone,
  • progesterone,
  • estrogen,
  • triiodothyronine (T3), and
  • thyroxine (T4)

Serum concentrations of the pituitary and end-organ hormones can now be assayed in commercial laboratories and replacement hormones are also readily available

Consequently, the old saying that pain, “cannot be measured” needs to be modified. Serum levels of the pituitary and end-organ hormones noted here serve as biomarkers for uncontrolled pain (see Table 3).

Table 3: Clinical features of Cushing’s Syndrome and the proportion of patients affected by these features

The Stimulation Phase

It is important to note that only severe pain will stimulate HPATG to the point that the end organs produce and secrete sufficient hormones to raise serum levels above normal

Studies show that patients with mild or intermittent pain, such as in common degenerative arthritis, have normal hormone serum levels.

This is an excellent practical point for the pain practitioner, since normal serum hormone levels usually mean that the patient’s pain is not in need of therapy with high-risk treatment, such as long-acting opioid drugs or invasive interventions.

Put another way, hormone serum levels are excellent biomarkers that help separate severe from mild pain. If end-organ serum hormone levels are above normal, however, enhanced pain-control treatment will be needed

If hormones are below normal levels, it is prudent to replace the hormones and achieve homeostasis before embarking on a therapeutic regimen that has risks, such as opioid-induced endocrine suppression

The Depletion Phase

If tissues in the hypothalamus, pituitary, adrenals, gonads, or thyroid cannot sustain the demands of severe pain, serum levels of some hormones may drop below normal levels

Based on the clinical experience to date, the most common end-organ hormones to diminish in the serum due to uncontrolled pain are

  • cortisol,
  • pregnenolone,
  • DHEA, and
  • testosterone

Once pain is controlled and/or hormones are replaced, serum levels will almost always return to normal.

Cortisol Abnormalities: The Most Serious Hormone Complications

Chronic cortisol abnormalities, when levels are either too high or too low, over an extended time period are the major hormonal problems in chronic pain patients. Although the prevalence of cortisol abnormalities in chronic pain patients is unknown, excess and deficient cortisol states are starting to be recognized among pain patients.

Extended periods of exposure to excess cortisol, often referred to as Cushing’s Syndrome, named after Harvey Cushing who first described the clinical signs and symptoms in patients with pituitary tumors, has serious complications

Complications include osteoporosis, hypertension, hyperlipidemia, and mental deficiencies. Until now, many of these complications in pain patients were simply viewed as unrelated, random events. 

The major complications that manifest in pain patients are

  • osteoporosis,
  • joint degeneration,
  • tooth decay,
  • hypertension,
  • hyperlipidemia,
  • obesity, and
  • mental deterioration.

In chronic pain patients, hypercortisolemia is usually episodic and only occurs during flares or periods of undertreatment that force the hypothalamus and pituitary to temporarily secrete ACTH and cortisol.

Physiologically, however, it makes little difference whether high serum cortisol levels are intermittent or constant, because chronic pain patients may experience high cortisol levels, even if intermittent, over long time periods and develop sustained complications.

It is very likely that joint degeneration, renal stones, vertebral collapse, hypertension, dementia, and hyperlipidemia so commonly observed in chronic pain patients are the results of intermittent hypercortisolemia over an extended period of time.

Of particular concern is that hypercortisolemia causes calcium resorption, which is the apparent cause of

  • osteoporosis,
  • dental erosion,
  • joint degeneration,
  • nephrolithiasis (renal stones) and
  • vertebral collapse

Hypocortisolemia produces weight loss, muscle wasting, mental apathy, hypotension, and, if not detected and treated, it may cause sudden death.

In patients who take opioids, testosterone is the major hormone suppressed, although opioids may also suppress cortisol. It is not known the precise opioid dosage or time frame necessary for suppression of testosterone and/or cortisol to occur.

Serum Testing and Replacement

Due to the two phases, stimulation and depletion, of pain’s effect on the HPATG system, practitioners should be prepared for either too high or too low serum hormone levels when they are assayed.

I would regard a cortisol level of less than 1.0 μg/dL to be a life-threatening emergency that requires immediate hormone replacement with hydrocortisone.

Replacement or partial replacement of 

  • hydrocortisone
  • pregnenolone
  • DHEA, or 
  • testosterone

is rightfully emerging as a new procedure in pain treatment

The benefits appear numerous. In early reports, less medication, particularly opioids, is required if hormone serum levels are normal prior to their initiation

Opioid Suppression of Hormones

Precise opioid dosages that may produce suppression have not been—and probably cannot be—determined due to individual biologic differences

It is the constancy of sustained-action opioids, however, that produces a 24-h blood and brain concentration that does not allow the HPATG to produce its usual, normal output of hormones.

Suppressed levels of testosterone are the most common problem with opioid administration, but cortisol, pregnenolone, and DHEA may also be suppressed

For reasons that are unclear, the thyroid hormones, T3 and T4, are seldom suppressed.

Testosterone suppression with long-acting and intrathecal opioids occurs in 75–85 % of patients.

Suppression may begin in the first 90 days of opioid administration and testosterone may remain suppressed as long as opioids are administered.

Given this extremely high prevalence, patients who take long-acting opioids need to be regularly screened for testosterone, as well as pregnenolone, DHEA, and cortisol

Replacement of these hormones should be done, as low serum levels of any of these hormones may be associated with poor pain control, including symptoms of allodynia and hyperalgesia

It is known that central sensitization and neuroinflammation due to glial cell activation are responsible for allodynia and hyperalgesia

Some hormones, particularly the glucocorticoids and sex hormones, have profound immune effects on the CNS

Hormone replacement has been reported to relieve allodynia and hyperalgesia in some patients.


The basic physiologic effect of pain on the endocrine system is one of severe stress.

Hormones, including cortisol, pregnenolone, DHEA, testosterone, and thyroid (T3 and T4) travel from their producing glands to distinct tissue targets, including injured nerves and the CNS

Hormones provide immunologic, anti-inflammatory, and regenerative properties for cellular protection and healing.

In the stimulation phase of severe pain, serum hormone levels are elevated. If pain persists unabated for too long, the hormonal system is unable to tolerate the stress of pain, and hormone production may be decreased causing serum hormone levels to drop below normal.

The most serious hormone complications of severe chronic pain are hyper- and hypocortisolemia. Cortisol serum levels rise and fall with emotion, exercise, nutrition, and disease states.

Hypocortisolemia may occur in severe, under-treated pain, and cortisol levels may drop below 1.0 μg/dL, which may be too low to sustain life.

Hormone serum levels serve as biomarkers for uncontrolled pain. Before embarking on therapy with long-acting opioids and other pain treatment modalities that carry risks, a minimal hormone assessment should be made to determine whether a chronic pain patient has normal serum levels of cortisol, pregnenolone, DHEA, and testosterone

Early clinical experience indicates that the use of opioids, and possibly other pharmaceutical agents, can be minimized if hormone homeostasis is achieved prior to introduction of these agents.

It is cautioned, however, that the patient’s report of pain and need for analgesic medication be paramount, and that hormone serum levels should never be the determinant of proper analgesia.


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