Opioid Endocrinopathy

Susan P. Demarest, MD; Ranjodh S. Gill, MD; Robert A. Adler, MD


Endocr Pract. 2015;21(2):190-198. 

In This Article

Abstract and Introduction


Objective The use of prescription opioids has increased dramatically over the past 20 years. Opioids appear to affect multiple endocrine pathways leading to abnormal levels of different hormones such as testosterone, cortisol, and prolactin (PRL). In this article, we review the current data regarding opioid effects on the hypothalamus, pituitary, and bone metabolism.

Methods We conducted a PubMed search for articles regarding opioids and each of the following subjects: testosterone, estrogen, cortisol, thyroid, growth hormone (GH), and bone. Most articles were primary source studies conducted between 1980 and 2014. Articles were included if studies were conducted within the time period, published in English, and available as full-length articles. Case reports were reviewed, but controlled studies were given more weight.

Results Opioids appear to affect each of the pituitary hormone pathways in addition to altering bone metabolism. The most commonly reported and substantial effect was hypogonadism in both sexes; however, suppression of the adrenal axis may be more common than initially thought. Although some studies report a change in thyroid and GH levels, overall effects have not been thoroughly studied. There is some evidence for increased fracture risk, possibly mediated by hypogonadism and fall risk.

Conclusion More research is needed to determine which opioids are more likely to cause endocrine dysfunction and which patients need to be screened and treated. Also unknown is the length of time to the development of hormonal changes after starting opioid therapy and if cessation of opioid therapy can normalize hormone levels.


Over the last 2 decades, the use of prescription opioids for chronic pain has dramatically increased, with estimated sales up 149% between 1997 and 2009.[1] The 2000 Joint Commission on the Accreditation of Health Care Organizations (JCAHO) guidelines for management of chronic pain included opioid use,[2] and extended-release opioid prescriptions increased from 9.3 to 22.9 million between 2002 and 2009. A 2010 Cochrane review showed that opioids reduce pain, but the degree of pain relief varied among studies, and quality of life and functional status were not necessarily improved.[3] Common side effects include constipation, nausea, pruritis, sedation, and headache.[4] Elderly Medicare patients on opioids have higher rates of falls, fractures, and hospitalizations compared to patients using nonopioid analgesics.[5] Opioids can also alter pain processing and can lead to hyperalgesia.[6]

Opioids exert their main analgesic effects through mu-opioid receptors in the brain, spinal cord, and peripheral nerves.[6] Opioid receptor subtypes are also found at various neural locations, which may mediate opioid effects ranging from beneficial analgesia to detrimental respiratory depression and gastrointestinal dysmotility. Receptors are also found within the hypothalamus and pituitary and mediate changes in hormonal release and regulation.[7] The majority of studies have focused on male hypogonadism; however, other hormone axes are often affected, and similar effects are found in both males and females.

The prevalence of hormonal derangements in patients on chronic opioids therapy is unknown, as is whether hormone replacement provides any benefit. There are few prospective studies or randomized controlled trials (RCTs) to determine the consequences of long-term opioid-induced endocrinopathy or the potential benefits of hormone replacement. We searched PubMed for primary studies, case reports, and reviews published between 1980 and 2014 to review the relationships among opioids, pituitary function, and bone metabolism. Only studies carried out in adults and published in English were included. Attempts were made to focus on RCTs, but most publications were cohort or retrospective studies. The potential effects of opioids are illustrated in Figure 1.

Figure 1.

Pituitary hormone pathways. A, Gonadal. B, Adrenal. C, GH. D, Thyroid. E, Prolactin. F, AVP. G, Bone. Stimulatory (+) and inhibitory (–) effects of opioids. ACTH = adrenocorticotropic hormone; AVP = arginine vasopressin; CRH = corticotropinreleasing hormone; DHEA = dehydroepiandrosterone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; T3 = triiodothyronine ; T4 = thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.