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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1122
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4313-4318
Copyright © 2006 by The Endocrine Society

Effects of Chronic Osteoarthritis Pain on Neuroendocrine Function in Men

Suzan Khoromi, Ranganath Muniyappa, Lisa Nackers, Nora Gray, Howard Baldwin, Kelli Anne Wong, Leigh Ann Matheny, Barbara Moquin, Aliya Rainer, Suvimol Hill, Alan Remaley, Laura Lee Johnson, Mitchell B. Max and Marc R. Blackman

Laboratory of Clinical Investigation (S.K., R.M., L.N., N.G., H.B., K.A.W., B.M., A.Ra., M.R.B.), Division of Intramural Research, National Center for Complementary and Alternative Medicine; Departments of Nursing (L.A.M.), Radiology (S.H.), and Laboratory Medicine (A.Re.), Warren Magnuson Clinical Center; Office of Clinical and Regulatory Affairs (L.L.J.), National Center for Complementary and Alternative Medicine; and Clinical Pain Research Section (M.B.M.), National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Suzan Khoromi, M.D., M.H.S., National Institutes of Health, Building 10, 4-1741, Bethesda, Maryland 20892-1302. E-mail: khoromisu{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Chronic pain has been associated with elevated cortisol, reduced LH and testosterone (T), and/or augmented circulating or excreted catecholamines. Most endocrine studies have been conducted in patients in whom the potentially confounding effects of depression, inflammatory disease, or coexistent medication use have not been controlled.

Objective: The objective of the study was to test the hypothesis that chronic pain activates ACTH-cortisol and suppresses LH-T.

Design and Setting: This was a case control study conducted at a clinical research center.

Participants: Participants included 16 opioid-naive men with chronic osteoarthritis pain, aged 35–65 yr with body mass index 20–30 kg/m2, and 12 healthy, opioid- and pain-free men of similar ages and body mass indexes.

Methods: We compared circulating concentrations of ACTH, cortisol, LH, and T derived from every 20-min blood sampling (2000–0800 h), and 24-h urinary excretion of cortisol, epinephrine, norepinephrine, and dopamine.

Results: There were no significant differences in mean or integrated concentrations of ACTH, cortisol, LH, or T, or in the corresponding approximate entropy scores in osteoarthritis patients, compared with control subjects. The 0800-h serum LH concentrations were elevated in patients vs. controls (6.42 ± 1.65 vs. 3.99 ± 1.54 IU/liter, mean ± SD, P = 0.02), whereas there were no significant group differences in total or free T, SHBG, cortisol binding globulin, dehydroepiandrosterone sulfate, or urinary cortisol and catecholamines.

Conclusions: These data suggest that neuroendocrine function is not significantly altered in otherwise healthy men with chronic musculoskeletal pain and that prior reports of such hormonal abnormalities may have resulted from the confounding effects of coexistent illness or medication use.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN CONTRAST TO the many reports of augmented activity of the hypothalamic-pituitary-adrenal (HPA) (1) and catecholaminergic (2) axes or suppressed gonadal steroid functions (3) in acute clinical and experimental pain, relatively little is known about the effects of chronic pain on the neuroendocrine system. Clinical and experimental studies of chronic pain have been conducted mainly in women with rheumatoid arthritis and fibromyalgia, in whom varying abnormalities of the HPA axis and gonadal function have been reported (4, 5, 6, 7).

Osteoarthritis (OA), a common, minimally inflammatory rheumatological syndrome characterized by chronic joint pain and dysfunction (8, 9), affects 9.6% of men and 18% of women over 60 yr of age (10) and has been the subject of several neuroendocrine investigations, mostly of the HPA axis. In one study, urinary free cortisol excretion was significantly lower in patients with chronic OA of the lumbosacral spine, compared with healthy volunteers (11). In another report of patients with mostly OA pain, only those individuals with concomitant psychiatric diagnoses failed to suppress cortisol in response to a dexamethasone challenge (12).

To date, most neuroendocrine studies in patients with chronic OA pain have included heterogeneous groups of men and women (13) with comorbid medical illness, depression (14, 15), and/or opioid or other medication use (16, 17, 18). To our knowledge, only one study has evaluated a well-characterized group of OA patients who did not have such comorbid confounders (19). In that report, there were no significant cortisol changes in male and female OA patients. There have been no prior evaluations of multiple neuroendocrine outcome measures in OA patients with chronic pain. In the current study, we assessed nocturnal ACTH, cortisol, LH, and testosterone (T) secretion, and 24-h urinary cortisol and catecholamine excretion, in a well-characterized group of men with chronic, moderate to severe, OA-related pain.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Of the 120 telephone responders with OA pain, 25 men qualified to come to the National Institutes of Health (NIH) Clinical Center for a complete screening evaluation. Seventeen of these men were eligible based on inclusion and exclusion criteria and completed the study. However, the data from one patient were excluded as a result of a subsequent positive urine drug screen. Of the 43 healthy volunteers who responded by telephone, 17 men qualified for a screening visit, of whom 12 were eligible and completed the study.

We evaluated 16 men with chronic pain (>3 months) due to OA. Pain was moderate to severe (>4 of 10), as self-assessed with a Likert scale (0 to 10) (20) using a daily pain diary for 2 wk before outpatient screening assessment. The clinical diagnosis of OA was further confirmed using Kellgren and Lawrence radiographic scoring criteria (21). Twelve healthy men without OA or other pain syndromes, of similar age and body mass index (BMI), were evaluated as control subjects (Table 1Go).


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  		TABLE 1. Characteristics of OA patients

 
OA patients and control subjects were excluded if they exhibited any of the following: endocrine dysfunction, inflammatory arthritis, fibromyalgia, congenital or developmental spinal disorder, depression at study entry as assessed by scores greater than 20 on the Beck Depression Inventory (BDI) (22), a history of sexual impairment, use of prescription opioids, systemic or injectable glucocorticoids, or illicit drugs or excess alcohol within 2 months before the study. Study participants were recruited between October 2004 and November 2005 through local newspaper advertisements at the NIH Clinical Center. This study was approved by the Institutional Review Board of the National Institute of Dental and Craniofacial Research. After giving informed written consent, study participants who satisfied the inclusion and exclusion study criteria underwent a complete physical examination and laboratory testing including antinuclear antibody titer, rheumatoid factor, C-reactive protein (CRP), and a urine drug screen. Functional ability was measured using the Oswestry Disability Index (23), and depression was measured with the BDI questionnaire (22).

Protocol

All study participants were admitted to the NIH Clinical Center inpatient unit at approximately 1700–1800 h on d 1. Subjects were offered a dinner of their choice between 1800 and 1900 h and were asked to refrain from drinking caffeine-containing beverages. At 1900 h, an iv catheter was inserted into a forearm vein and kept open with heparinized (1000 U/liter) 0.9% sodium chloride. From 2000 to 0800 h, blood samples (3 ml) were collected at 20-min intervals for ACTH, cortisol, LH, and T determinations. All subjects were encouraged to sleep beginning at 2300 h, and room lights were turned off from 2400 to 0700 h, although sleep was not monitored. At 0800 h on the morning of d 2, after an overnight fast, blood was collected for measurements of SHBG, cortisol binding globulin (CBG), and dehydroepiandrosterone sulfate (DHEAS). All plasma and serum samples were stored at –80 C until assayed. Beginning at 0800 h on the day of admission, a 24-h urine sample was collected for determination of urinary free cortisol, epinephrine, norepinephrine, and dopamine.

During the study, participants were asked to refrain from using analgesic medications, including antiepileptic drugs, tricyclic antidepressants, selective serotonin reuptake inhibitors, and benzodiazepines. They were also requested to avoid starting new therapies for pain relief, including local joint injections with steroids and complementary and alternative modalities, except for glucosamine and chondroitin. They were allowed to use acetaminophen and nonsteroidal antiinflammatory agents for analgesic relief.

Biochemical measurements

We used a chemiluminescence competitive binding assay to measure plasma levels of cortisol [Nichols Institute Diagnostics, Inc., San Juan Capistrano, CA; sensitivity 13.7 nmol/liter (0.5 µg/dl); intraassay coefficient of variation (CV) 5.5%; interassay CV 9.3%] and a solid-phase, two-site sequential chemiluminescent immunometric assay to determine plasma ACTH levels [Diagnostic Products Corp., Los Angeles, CA; sensitivity 1.1 pmol/liter (5 pg/ml); intraassay CV 2.3%; interassay CV 2.8%]. CBG was measured by RIA with a sensitivity of 0.5 mg/dl and intra- and interassay CVs of 7.9 and 7.7%, respectively. Total T (TT) concentrations were measured by ELISA using commercial kits from ALPCO Diagnostics (Salem, NH). Sensitivity and intra- and interassay CVs were 0.48 nmol/liter (14 ng/dl) and 5.3 and 9.6%, respectively. Serum LH was measured by ELISA using commercial kits (Diagnostic Systems Laboratories, Webster, TX.). Sensitivity and intra- and interassay CVs were 0.1 IU/liter and 4.4 and 8.7%, respectively. SHBG was measured by chemiluminescent immunometric assay with a sensitivity of 2 nmol/liter, and intra- and interassay CVs were 2.8 and 6.6%, respectively. Free T (FT) was calculated as described by Vermeulen et al. (24) using a second-order equation based on SHBG, TT, and albumin concentrations. Twenty-four-hour urinary excretion of catecholamines and cortisol was measured by HPLC under a contract between the NIH Clinical Center and an outside commercial laboratory (Mayo Medical Laboratories, Rochester, MN). Reference ranges for urinary tests are as established by the commercial laboratory that performed these measurements. Serum levels of DHEAS were measured by the NIH Clinical Center’s Department of Laboratory Medicine. The DHEAS assay sensitivity was 0.40 µmol/liter (0.14 µg/ml) with intra- and interassay CVs of 7.6, and 9.5%, respectively. Serum concentrations of CRP were measured in the NIH Clinical Center’s Department of Laboratory Medicine by routine high sensitivity nephelometric assay on an IMMAGE Immunochemistry System (Beckman Coulter, Fullerton, CA). The sensitivity was 0.1 mg/dl, and the intra- and interassay CVs are 2.6 and 3.0%, respectively.

Analysis of hormone secretion

Cluster analysis. Pulse analyses of plasma ACTH, cortisol, serum LH, and T were performed using Cluster, a well-characterized and validated pulse detection algorithm (25). Significant pulsatile events were detected by a moving 2 x 2 (test nadir and peak sample numbers) cluster configuration for ACTH and T and a 2 x 1 cluster for cortisol and LH, respectively, with a pooled t statistic value of 2.0 and 2.0 for significant upstrokes and downstrokes. These parameter settings were chosen to limit the false-positive detection rate to less than 5%. The following pulse attributes were determined: maximal peak height, highest absolute concentration attained in the pulse; nadir, the prepeak (mean) hormone concentration; incremental peak amplitude, algebraic difference between maximal peak height and prepeak nadir; area under the peak; and pulse frequency, the number of significant peaks identified per 12 h (25).

Approximate entropy (ApEn)

We calculated ApEn of the individual subject’s ACTH, cortisol, LH, and TT concentration-time series. ApEn refers to the regularity or orderliness of hormone release, with a higher entropy reflecting a more random or disordered pattern of hormone secretion (26).

Outcome measures

The primary outcome variables in this study were the mean and integrated LH, TT, ACTH, and cortisol concentrations derived from the overnight blood sampling procedures. Secondary outcome measures included: 1) all other hormone secretory parameters obtained during the nocturnal blood sampling; 2) morning levels of TT, FT, LH, ACTH, and cortisol, as derived from the last three blood samples collected between 0700 and 0800 h; 3) morning levels of SHBG, CBG, and DHEAS; 4) pain as measured by the Likert numerical pain scale (0 to 10) in all of the involved joints each day at bedtime for 2 wk before hospital admission (20) and the highest scores reported were used for data analysis; and 5) scores on the BDI (22) and the Oswestry Disability Index (23) obtained at the end of the inpatient visit from all subjects.

Statistical analysis

All experimental results were coded and entered into a secured database in a study computer. Linear regression was used to model the primary and secondary hormone outcomes, adjusting for age and BMI as continuous variables. All hormones were natural log transformed and assumptions checked. Sensitivity analyses and analyses including the participant excluded for a positive urine drug screen were run to assess the potential influence of missing data due to the cluster analysis program not converging or a participant not completing the Oswestry or Pain Visual Analog Scale (WVAS) instruments. Sensitivity analyses did not find statistically significant results. The excluded participant did not influence the analyses. Complete data analyses and P values from adjusted models are presented. Geometric means and SD values are from unadjusted models. Excel and S-PLUS 6.2 for Windows (Insightful Corp., Seattle, WA) were used for all analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Characteristics of study participants

As shown in Table 1Go, OA patients and healthy men were similar in age and BMI. All patients suffered from moderate to severe OA by both clinical and radiographic criteria, with 13.0 yr of average disease duration, a mean pain score of 5.46, and a substantially elevated Oswestry index. Eight patients suffered from OA of the knee, five of the lumbosacral spine, three of the hip, three of the foot, three of the shoulder, and four of the hands. At some point in the past, 13 patients had used nonsteroidal antiinflammatory agents, two serotonin reuptake inhibitors, and five complementary and/or alternative modalities for pain control. Although the BDI scores were significantly greater in the patients than in the healthy control subjects, the average score in OA patients was well below the scores associated with clinically significant depression (22). Serum concentrations of CRP, determined in the morning after an overnight fast, were normal and similar in OA patients and control subjects (0.17 ± 0.22 vs. 0.31 ± 0.44, respectively, P = NS).

Nocturnal blood sampling

Overnight mean and integrated concentrations for ACTH, cortisol, LH, and TT are illustrated in Tables 2Go and 3Go. There were no statistically significant differences in mean and integrated values for ACTH, cortisol, LH, or TT in OA patients, compared with healthy control subjects.


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  		TABLE 2. Cluster analysis of ACTH and cortisol concentrations

 

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  		TABLE 3. Cluster analysis of LH and T concentrations

 
Further analysis of overnight ACTH and cortisol secretion revealed that ACTH peak area and incremental ACTH peak height were both lower in patients with OA than in healthy men (P = 0.024 and P = 0.019, respectively). In contrast, there were no significant differences in any cortisol secretory measure between the two groups (Table 2Go). None of the measured nocturnal LH and TT secretory indices differed significantly between OA patients and control subjects (Table 3Go).

Other outcome measures

Morning concentrations of LH were higher in OA patients, compared with controls (6.42 ± 1.65 vs. 3.99 ± 1.54 IU/liter, respectively, P = 0.02), whereas there were no significant group differences in FT, SHBG, ACTH, cortisol, CBG, or DHEAS (Table 4Go), or 24-h excretion of cortisol or catecholamines (Table 5Go). In addition, there were no significant relationships of overnight hormone indices, morning hormone levels, or 24-h urine hormone excretion with mean pain scores, BDI scores, or Oswestry Disability Index in OA patients (data not shown).


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  		TABLE 4. Hormonal measurements at 0800 h

 

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  		TABLE 5. Twenty-four-hour urinary excretion of cortisol, epinephrine, norepinephrine, and dopamine

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first detailed report of neuroendocrine function in men with chronic, moderate to severe OA pain. We detected no significant group differences in 12-h overnight mean or integrated concentrations of ACTH, cortisol, LH, and T; morning levels of ACTH, cortisol, T, SHBG, CBG, or DHEAS; or urinary excretion of cortisol or catecholamines between OA patients and healthy men of similar ages and BMIs. In comparison, values for the ACTH peak area and incremental ACTH peak height were lower, and morning levels of LH somewhat higher, in OA patients, compared with control subjects. Finally, we found no significant relationships between overnight hormone indices, morning hormone levels, or 24-h urine hormone excretion with measures of quality of life in the OA patients.

In contrast to the present study findings in patients with chronic pain, investigations of acute pain in man and animals have generally revealed increases in CRH, ACTH, cortisol (1), arginine-vasopressin, and catecholamines (2) and decreases in T (3, 27). In regard to chronic pain, clinical neuroendocrine studies have been reported primarily in patients with rheumatoid arthritis and fibromyalgia, disorders that are more common in women. Rheumatoid arthritis, a chronic inflammatory systemic and articular disorder, has been associated with subnormal ACTH and cortisol responsivity to exogenous CRH administration (4, 28) and decreased spontaneous cortisol secretion (5, 29) and with disruptions in its normal circadian rhythm (30). Fibromyalgia, a rheumatological condition characterized by widespread musculoskeletal pain (31), has been associated with multiple HPA axis abnormalities (6, 7) including disrupted cortisol circadian rhythm with elevated nocturnal plasma concentrations (32), marked hypersecretion of ACTH, and hyposecretion of CRH (33) and with unchanged urinary excretion of norepinephrine and epinephrine (34).

To date, most studies evaluating neuroendocrine accompaniments of OA pain have included patients with neuropathic, postsurgical, and cancer pain (13), often in association with depression (12, 16). Moreover, most neuroendocrine studies of chronic pain have not evaluated men and women separately (11, 35) despite the known gender dimorphism in pain perception (36). To our knowledge, only one study has reported a group of patients with OA pain who did not have comorbid conditions such as cancer or depression or use chronic opioidergic or other endocrine-disrupting medications (19). In that report, male and female OA patients, evaluated together, exhibited a nonsignificant trend to increased morning and altered circadian cortisol levels, as assessed by thrice-daily blood collections (19). In the present study, we found that peak ACTH area and incremental ACTH peak height were slightly, but significantly, lower and morning values for LH somewhat higher, in OA patients, compared with healthy control subjects. The reductions in the aforementioned indices of ACTH secretion suggest that peak ACTH release is slightly reduced in OA patients vs. healthy control subjects. The latter may have resulted from a decrease in hypothalamic stimulation of ACTH, reduced corticotropic responsivity to CRH, or other factors. Although we did not assess endogenous opioid tone in this study, it is possible that enhanced action of endogenous opioids in men experiencing chronic pain due to OA may contribute to decreased CRH production, with consequent suppression of peak ACTH secretion (37). Of note, however, was the fact that mean and integrated ACTH concentrations did not differ significantly between OA patients and control subjects, suggesting that the modest differences in nocturnal peak ACTH area and incremental ACTH peak height were of little to no physiological consequence.

We detected significantly higher morning concentrations of LH without concomitant differences in TT or FT in men with OA, compared with healthy men. Similarly, we observed that overnight mean and integrated LH concentrations were higher, albeit nonsignificantly, whereas the corresponding concentrations of T did not differ in OA patients vs. controls. Taken together, these findings are compatible with the presence of incipient, or compensated, primary hypogonadism in our OA patients. We are unaware of previous reports of LH or T abnormalities in men with chronic OA pain. Prior studies have reported decreases in total and/or bioavailable serum T levels in an experimental model of acute pain in young male rats (27) and men with acute myocardial infarction (3). Men with chronic pain due to rheumatoid arthritis have been reported to exhibit low basal morning (38, 39) and hCG-stimulated T levels (40) and nonelevated LH levels (38), presumably as a consequence of the augmented proinflammatory cytokine environment. By comparison, in one study, women with fibromyalgia and chronic pain exhibited reduced estradiol levels and nonelevated LH in the morning as well as decreased LH responsivity to GnRH stimulation (41), suggesting a central hypogonadism, whereas no abnormalities in baseline estradiol, LH, or FSH were observed in a larger group of premenopausal or postmenopausal women with fibromyalgia (42).

The present study differs from prior investigations in patients with chronic pain in a number of its features. First, because of the gender dimorphism in the experience of pain (36) and the potentially differential effects of gender on the HPA, sex hormone, and catecholaminergic axes, we limited the study to men. Second, we chose a relatively homogeneous group of patients with OA. OA is considered to be a minimally inflammatory condition, wherein circulating concentrations of proinflammatory cytokines tend to be normal, albeit in the setting of signs of synovial inflammation (8, 9, 43). We detected no significant differences between OA patients and control subjects in morning serum levels of CRP, using a high-sensitivity assay, suggesting that systemic inflammation was not present in our OA patients. Moreover, the presence of normal and similar concentrations of ACTH and cortisol (mean and integrated ACTH) in the OA and control groups suggests that resistance to the actions of glucocorticoids was unlikely in our OA patients. Third, because OA pain intensity is known to fluctuate through the day with lower pain levels reported at 1500–1600 h (44) and because an average of 7–14 pain scores gives a more accurate estimate of true mean pain than a single measurement or additional scores in the setting of chronic pain (45), patients were asked to keep a log of their pain average once at bedtime for 14 d at the time of study entry (45). Fourth, we studied only men with moderate to severe pain, thus minimizing the likelihood of false-negative results. Fifth, we assessed the ACTH-cortisol, LH-T, and catecholaminergic axes in all patients and controls by overnight frequent blood sampling and 24-h urinary collections, whereas other studies reported fewer endocrine outcome measures.

Several limitations of this study deserve comment. Because of strict inclusionary and exclusionary criteria, comparatively few OA patients were evaluated; nonetheless, our study was sufficiently powered (a priori) to detect significant differences in the primary outcome measures between the patient and control groups. The relative homogeneity of our study population does not allow for extrapolation of our findings to women or patients with non-OA chronic pain. Quantitative and qualitative changes in circadian rhythms of the hormones measured could not be ascertained fully because 24-h blood sampling was not performed, and quality and quantity of sleep were not measured. Finally, catecholamines were quantified only in urine and not in blood.

Taken together, the current findings suggest that neuroendocrine function is not appreciably altered in otherwise healthy men with chronic pain due to OA and that prior reports of hormonal abnormalities in men with chronic pain may have resulted from the confounding effects of coexistent illness or medication use. Further studies appear warranted to investigate 24-h secretory patterns of LH and gonadal steroids in men and women with diverse etiologies of chronic pain.


   Acknowledgments
 
The authors thank Ms. Mary Ryan (NIH medical library information specialist) for her invaluable assistance in the preparation of this manuscript and Drs. Salvatore Alesci and Raymond Dionne for their constructive comments on reviewing this work.


   Footnotes
 
This investigation was supported by the Intramural Research Programs of the National Center for Complementary and Alternative Medicine and the National Institute on Dental and Craniofacial Research and the Clinical Center of the National Institutes of Health (Bethesda, Maryland).

Disclosure summary: The authors have nothing to disclose.

First Published Online August 15, 2006

Abbreviations: ApEn, Approximate entropy; BDI, Beck Depression Inventory; BMI, body mass index; CBG, cortisol binding globulin; CRP, C-reactive protein; CV, coefficient of variation; DHEAS, dehydroepiandrosterone sulfate; FT, free T; HPA, hypothalamic-pituitary-adrenal; OA, osteoarthritis; T, testosterone; TT, total T.

Received May 24, 2006.

Accepted August 9, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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