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Ask the Expert: Should You Test For and Treat Opioid-induced Hypogonadism?

November/December 2013.
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Question: Should you test for and treat opioid-induced hypogonadism?

Answer: Opioid-induced endocrinopathy, specifically hypogonadism, is a physiological side effect in which opiate use suppresses the sex hormones, among other substances.1,2 Two mechanisms for this have been theorized. One is that opioid use alters gonadotropin pulse patterns, affecting plasma testosterone and other adrenal and gonadal hormones. Another is that the anterior pituitary, which controls testosterone, along with growth hormone (GH), prolactin, thyroid stimulating hormone (TSH), adrenalcorticotrophic hormone, luteinizing hormone (LH), and follicle stimulating hormone, has an altered response to gonadrotropin-releasing hormone.1 Put simply, opioids generally and acutely increase GH, TSH, and prolactin, and decrease LH, testosterone, estradiol, and oxytocin.1 Chronic opioid use, however, may not lead to this pattern.3-5

In patients taking opioids, both sexes are affected—although males may be more susceptible.4-6 Symptoms in males may present as delayed ejaculation and erectile dysfunction.2-4 Women may experience amenorrhea or oligomenorrhea.7,8 Men and women may experience decreased libido, osteopenia, osteoporosis, fatigue, decreased muscle mass, and increased fat deposits.

The Endocrine Society recommends treating symptomatic patients who complain of these symptoms.9

Some Relevant Clinical Trials

Italian researchers studied whether the opioid-reversal agent naltrexone would have a positive effect on male sexual function.10 In a single-blind prospective study of oral naltrexone administered to men with hypogonadism, subjects reported more episodes of coitus per week, for the first 7-15 days, but, erectile capacity returned to baseline upon discontinuation of naltrexone. Serum testosterone levels were unchanged. This study implies there is a centrally-mediated aspect to opiate-induced hypogonadism.10

The TRiUS trial investigated the effects of testosterone replacement in opiate-induced low testosterone patients.11 There was no specific goal relating to serum testosterone level, although serum testosterone levels were measured. In this observational study, both opiate users and non-opiate users were prescribed Testim 1%. They were evaluated for testosterone serum levels along with sex hormone binding globulin.11 The authors concluded, “Testosterone replacement therapy increased serum testosterone in hypogonadal opioid users and non-users alike.” The data suggest that testosterone replacement might result in similar improvements in sexual function and mood for hypogonadal opioid users as for non-users.”11

Two other reported studies show the benefits of testosterone replacement in opioid-induced hypogonadism.12,13 Testosterone replacement for up to a year improved symptoms and serum levels.12 The authors concluded that “a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient’s quality of life, an important clinical aspect of pain management.”12

Treatment Recommendations

The Endocrine Society recommends that hypogonadal males be treated with testosterone to improve sexual drive and performance, increase bone mineral density, increase muscle mass, and decrease fat mass.9 The Veterans Administration guidelines on management of opioid therapy for chronic pain do not specifically recommend how to test or when to treat with testosterone but recommend monitoring for sexual and mental health symptoms biannually.14 Some clinicians recommend that the goal of testosterone therapy target a patient’s specific symptoms, whereas others believe it also is necessary to bring testosterone serum levels into normal range.2,5,15,16 In pain management, symptom relief alone usually is not a reliable or stand-alone measure since pain patients ill enough to require opioids routinely suffer fatigue, depression, muscle wasting, and loss of sex drive unrelated to hormone levels. Consequently, testosterone serum testing and replacement when a deficiency is found is emerging as a routine measure for many pain specialists treating opioid-
maintained pain patients.2,5,14

Female pain patients with low testosterone levels may also require testosterone replacement.17 Recommended dosages are about 20% to 30% of commercially-prepared male formulations. Human chorionic gonadotropin (HCG) carries a label of treating hypogonadism, and it may be a substitute or adjunctive treatment for low testosterone, particularly in females. Dehydroepiandrosterone (DHEA) is a testosterone precursor that also may raise serum testosterone levels. Consequently, it may be used as an adjunct to HCG and/or testosterone therapy.

Contraindications against treating hypogonadism with testosterone therapy include breast or prostate cancer, a palpable prostate nodule; high risk for prostate cancer (African-Americans or men with first-degree relatives with prostate cancer); untreated severe obstructive sleep apnea; severe lower urinary tract symptoms; uncontrolled or poorly controlled heart failure; or the desire to preserve fertility.9

Special Pain Issues

Beyond its role in sexual performance, testosterone plays a much wider and critical role in pain management. Testosterone enhances analgesia, healing, and the immune response.5,7,18-22 It also is critical for prevention of osteoporosis, depression, and immobility.5,16 Without adequate serum testosterone levels, pain patients may complain of not only weakness, fatigue, depression, and loss of libido, but poor pain control, hyperalgesia, and loss of effectiveness of their opioid medications. Long-acting and intrathecal opioids tend to be more suppressive than short-acting opioids.23 Consequently, it now is suggested that pain patients maintained on opioids, particularly those on long-acting or intrathecal opioids, must be periodically tested for serum testosterone deficiency.3,5,23 Replacement will be necessary if low serum levels are detected. This applies to males and females.17,24


Male and female pain patients who are maintained on daily opioids, particularly those who are on long-acting or intrathecal opioids, should be periodically tested for low serum testosterone levels. If low levels are found, testosterone replacement is highly recommended. Opioid-maintained patients who complain of poor pain control, loss of opioid effectiveness, or hyperalgesia also should be evaluated, and if a deficiency is found, replacement is warranted.



Jason A. Morell, PharmD

PGY-1 Pharmacy Resident

OSF St. Francis Medical Center

Peoria, Illinois


McKenzie C. Ferguson, PharmD, BCPS

Assistant Professor, Pharmacy Practice

Last updated on: May 30, 2014
First published on: December 1, 2013