‘‘(Opium) has kept, and does now keep down the population: the women have fewer children than those of other countries, the feeble opium-smokers of Assam are more effeminate than women.''

— Charles Alexander Bruce, ‘‘Report on the manufacture of tea and on the extent and produce of the tea plantations in Assam.'' Calcutta, 1839.

Opioids have been used for medicinal and analgesic purposes for centuries.1 However, their negative effects on the endocrine system are barely addressed in modern medicine. Hypogonadism is a well known endocrine side effect of short and longterm opioid use—low serum testosterone concentrations in male heroin and methadone users were first reported in the 1970s.2 However, presence of hypogonadism is largely ignored since many of the symptoms and signs of hypogonadism are eclipsed by the discomfort and common symptomatology caused by chronic pain.

In this brief review, we will discuss the pathophysiology, signs and symptoms, approach to diagnosis, and treatment of hypogonadism as a guide to aid clinicians in diagnosing and treating this common side effect of long-term opioid use.

Pathophysiology of Opioid-Gonadal Axis

The hypothalamic-pituitary-gonadal (HPG) axis controls the production of the primary sex steroids, testosterone (androgen) and estradiol (estrogen). It begins with the secretion by the hypothalamus of gonadotropin releasing hormone (GnRH). GnRH stimulates the anterior pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). These two hormones are released into the systemic circulation and stimulate the gonads—the testes and ovaries—to secrete testosterone or estradiol, respectively. It should also be noted that the testes through the aromatization of testosterone also secrete estradiol and that testosterone is secreted by the ovarian theca cells. These sex hormones then exert a negative feedback on the hypothalamus and pituitary to control the secretion of GnRH, LH, and FSH. Testosterone and estrogen are essential for normal sexual and reproductive development and behavior.1

The function of the HPG axis is under the influence of multiple factors including opioids, both endogenous and exogenous, as opioid receptors are present in the hypothalamus, pituitary and on testicular tissue.3 Stimulation of opioid receptors in the hypothalamus resulting in tonic inhibition of secretion and interference of pulsatility GnRH is well documented, though opioids may also have a direct effect on the pituitary gland and the testes. Occasionally opioids result in elevated prolactin levels and thereby resulting in decrease production of testosterone. Hyperprolactinemia, like opioids, tonically inhibits the secretion of GnRH.1 In addition, opioids have also been shown to alter the adrenal production of dehydroepiandrosterone (DHEA), an important precursor of both testosterone production in men and estradiol in women.4

Several animal and human studies have investigated the influence of opioids on the hypothalamic-pituitary-gonadal axis. Depending on the studied population, the reported prevalence of opioid induced hypogonadism ranges from 21 percent to 86 percent.5 This wide range in prevalence, in addition to baseline status of the patient, is dependent on the dose, duration, and route of administration of the opioids. In one study, testosterone concentrations dropped by more than 50 percent within a few hours of taking an opioid, and returned to baseline within 24-72 hours after withdrawal; depending on the dose used, it can take up to a month to recover.6

Diagnosis

Physicians should inquire before initiating and on subsequent visits about symptoms and signs of hypogonadism in all patients about to receive high-dose or long-term opiods. These include fatigue, decreased libido, erectile dysfunction, depression, night sweats, decreased muscle mass, infertility, anemia, insomnia and osteoporosis. Despite these symptoms being fairly specific for hypogonadism, these symptoms are often observed in patients with chronic pain, owing to a possible missed diagnosis. In the presence of suspicion, a laboratory work-up including both free and total testosterone, as well as a serum prolactin level is a reasonable start, as these are the most common etiologies for hypogonadism. Total testosterone values, however, must be interpreted carefully in the aging male because sex hormone-binding globulin (SHBG) levels might be elevated. If the total testosterone level is normal in the aging male presenting signs of hypogonadism, the clinician can rely on free testosterone or measure SHBG and calculate bioavailable testosterone.7

Treatment

Patients with symptoms of hypogonadism who are confirmed to be hypogonad require treatment. First, we suggest rotating opioids, decreasing doses (if applicable) and seeking alternate forms of pain control before starting testosterone therapy. If patients continue to remain hypogonad after opioid rotation, testosterone replacement should be initiated. Replacement can be achieved in a multitude of forms: transdermal patch, transdermal gel, and intramuscular injections (see Table 1). We recommend checking a baseline complete blood count (CBC), prostate specific antigen (PSA) and a digital rectal examination (DRE) before initiation of testosterone replacement and at subsequent visits.

Testosterone replacement therapy should be discontinued per Endocrine Society guidelines on any individual who develops the following: a hematocrit value > 54%, a PSA > 4ng/mL, an increase in PSA of 1.4ng/mL within any 12-month period or a PSA velocity of more than 0.4ng/ mL/yr using the PSA level after six months of testosterone administration.8 Any patient who has to have testosterone therapy discontinued should seek evaluation by a Urologist to further investigate possible prostate pathology.

Conclusion

Opioid-induced hypogonadism is a common complication of therapeutic or illicit opioid use. Patients on long-term opioid therapy should be actively monitored for signs and symptoms consistent with hypogonadism. In cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, and/or testosterone hormone supplementation after careful consideration of the risks and benefits.

Kevin Donohue, DO, is an Endocrine Fellow, Thomas Jefferson University Hospital, Philadelphia.

Intekhab Ahmed, MD is Clinical Associate Professor, Jefferson Medical College, Philadelphia

Jeffrey L. Miller, MD is Clinical Associate Professor, Jefferson Medical College, Philadelphia

Steven Mandel, MD is Professor of Neurology and Anesthesiology, Jefferson Medical College, Philadelphia.

Adam Sobel, MD, is an Instructor, Jefferson Medical College, Philadelphia.

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