Introduction to Fast Fact #284     Opioid-induced androgen deficiency (OPIAD) is a common, yet underdiagnosed, consequence of prolonged opioid therapy; this Fast Fact will review OPIAD.

Demographics   Biochemical and clinical hypogonadism have been observed in patients receiving intrathecal, transdermal, and sustained-release opioids [1]. Hypothalamic-pituitary-gonadal axis (HPA) suppression has been demonstrated within hours of methadone exposure, but risk appears to increase with increasing doses for extended durations. Some studies have found a dose-response effect with increased testosterone suppression at higher opioid doses [2,3]. As many as 50-100% of patients receiving daily opioid doses equivalent to 100-200 mg oral morphine for more than one month will have some degree of OPIAD [4,5].  OPIAD prevalence appears to be influenced by type of opioid used and may be least prevalent with buprenorphine (6).  In one observational study, 89% had biochemical evidence of hypogonadism, and 87% reported severe erectile dysfunction or diminished libido after starting opioids despite normal erectile dysfunction before using opioids [7]. One study found that men may have higher prevalence of hypogonadism than women [8]. Teenage patients have not been studied.

Physiology     OPIAD results primarily from suppression of the HPA and is a form of secondary (hypogonadotropic) hypogonadism. Opioids inhibit secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus, leading to decreased sex hormone secretion [4,5]). Opioids may also decrease adrenal androgen synthesis and directly inhibit testicular testosterone synthesis [4,7].

Symptoms and signs     Hypogonadism can cause decreased libido, erectile dysfunction, decreased fertility, fatigue, irregular menstrual cycle, weight gain, depression, osteoporosis, or hot flashes [4,5]. Physical findings include decreased facial and body hair, reduced muscle mass, increased body fat, and small or shrinking testes [5,8].

Diagnosis   Because the incidence is high and data about dosing thresholds is unknown, OPIAD should be considered in any patient on opioids with signs or symptoms of hypogonadism [5]. However, many of the symptoms of OPIAD are also caused by advanced illnesses, making it difficult to attribute them appropriately. There are no data to guide decision-making about OPIAD in advanced illness. It is reasonable to limit clinical evaluation of OPIAD to patients whose prognoses are judged to be sufficiently long enough to benefit from OPIAD treatment [9]. Collaboration with an endocrinologist is advised. 

• Men: Test the total serum testosterone drawn at 8 am (normal range in most laboratories is 300 to 800 ng/dl). If abnormal or borderline, repeat the test at 8 am once more (as levels may fluctuate). Obesity and older age reduce hormone binding proteins and can interfere with results. Additional confirmatory testing includes free testosterone, serum hormone binding globulin, LH, FSH, and prolactin [4,8].
• Women: There are currently no established diagnostic criteria in women. Women with symptoms of OPIAD should be referred to an endocrinologist.

Management   There is no direct evidence as to whether OPIAD improves with opioid rotation or dose reduction (short of cessation).  Since improvement of other opioid side effects vary among patients with opioid rotation or dose reduction, these may be attempted [2]. Buprenorphine should not impact pituitary trophic hormones as much as full agonist opioids, however, long-term effects of buprenorphine on the HPA axis are lacking (10).

Testosterone replacement   Cessation of opioid therapy can lead to recovery of normal serum testosterone levels within days of discontinuation [5]. Testosterone replacement therapy for women is not FDA approved but may be appropriate for some patients [5]. Management of OPIAD in women who need to remain on opioid therapy is not established and is best managed by an endocrinologist.
For men who need to remain on opioid therapy, testosterone replacement is the mainstay. It may be administered by intramuscular injections, buccal tablets, or transdermal patches, gels, or creams [4,5]. Measurable improvements in depressed mood and energy have been documented after 12 weeks of testosterone therapy [6,10-12].  Doses and frequencies vary by route and dosage form.  

• Precautions:  Testosterone treatment is not recommended in patients who have or at high risk of breast or prostate cancer [9].
• Adverse effects: Polycythemia, decreased HDL, hypoglycemia, hypercalcemia, edema, acne, gynecomastia, headache, mood swings, BPH, increased mortality, MI, venous thromboembolism, and stroke have been associated with testosterone therapy (13,14).
• Monitoring:  Effects of testosterone therapy typically occur within the first three to six months of treatment [9].Therefore, serum testosterone levels should be measured 3-6 months after starting testosterone therapy and then annually. Close collaboration with an endocrinologist is advised.

Conclusion   OPIAD is an under-diagnosed consequence of prolonged opioid therapy, and untreated patients may have reduced quality of life. Men who are diagnosed with OPIAD may be treated with testosterone therapy with appropriate monitoring. Diagnosis and treatment of OPIAD in women is not well established and should be referred to an endocrinologist.

References 

1. Daniell, H.W., Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain, 2008. 9(1): p. 28-36.
2. Katz, N. and N.A. Mazer, The impact of opioids on the endocrine system. Clin J Pain, 2009. 25(2): p. 170-5.
3. Mendelson, J.H., J.E. Mendelson, and V.D. Patch, Plasma testosterone levels in heroin addiction and during methadone maintenance. J Pharmacol Exp Ther, 1975. 192(1): p. 211-17.
4. Colameco, S. and J.S. Coren, Opioid-induced endocrinopathy. J Am Osteopath Assoc, 2009. 109(1): p. 20-5.
5. Smith, H.S. and J.A. Elliott, Opioid-induced androgen deficiency (OPIAD). Pain Physician, 2012. 15(3 Suppl): p. Es145-56.
6. Kafel H, Braga-Basaria M, Basara S.  Opioid-induced androgen deficiency in men: prevalence, pathophysiology, and efficacy of testosterone therapy.  Andrology 2025;
7. Daniell, H.W., Hypogonadism in men consuming sustained-action oral opioids. J Pain, 2002. 3(5): p. 377-84.
8. 8. Fraser, L.A., et al., Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes, 2009. 117(1): p. 38-43.
9. 9. Bhasin, S., et al., Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2010. 95(6): p. 2536-59.
10. 10. Varma A, Sapra M, Iranmanesh. Impact of opioid therapy on gonadal hormones: focus on buprenorphine. Hormone Molecular Biology and Clinical Investigation. 2018; 36(2):20170080.
11. Basaria S, Travison TG, Alford D, et al.  Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial. Pain 2015; 156(2):280-288.
12. 11. Daniell, H.W., R. Lentz, and N.A. Mazer, Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency. J Pain, 2006. 7(3): p. 200-10.
13. 12. Traish, A., A.T. Guay, and R.F. Spark, Are the Endocrine Society’s Clinical Practice Guidelines on Androgen Therapy in Women misguided? A commentary. J Sex Med, 2007. 4(5): p. 1223-34; discussion 1234-5.
14. 13. Vigen, R., et al., Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. Jama, 2013. 310(17): p. 1829-36.
15. Glueck CJ, Goldenberg N, Wang P.  Testosterone therapy, thrombophilia, venous thromboembolism, and thrombotic events.  J Clin Med 2019; 8(1):11.

Conflicts of Interest Disclosure: the authors have disclosed no relevant conflicts of interest.
Authors’ Affiliations: Ohio State College of Medicine, Columbus, OH.
Version History:  First published September 2014. Re-copy-edited in September 2015; reviewed and updated again in February 2025.