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The Impact of Opioids on the Endocrine System

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The Impact of Opioids on the Endocrine System REVIEW ARTICLE The Impact of Opioids on the Endocrine System Nathaniel Katz, MD, MS* and Norman A. Mazer, MD, PhDw barely discussed in the modern medical lexicon, opioids Objectives: Opioids have been used for medicinal and analgesic have negative effects on the endocrine system, which have purposes for centuries. However, their negative effects on the been observed for at least a century. These effects (Table 1) endocrine system, which have been known for some times, are include decreased testosterone production in men, with loss barely discussed in modern medicine. Therefore, we conducted a of libido and other expected effects, and menstrual systematic review of the impact of opioids on the endocrine system. irregularities and infertility in women. In view of the Methods: A review of the English language literature on preclinical increased use of opioids for chronic pain, it has become and clinical studies of any type on the influence of opioids on the increasingly important to recognize and manage their endocrine system was conducted. Preliminary recommendations endocrine complications. for monitoring and managing these problems were provided. Results: Long-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symp- toms of opioid-induced hypogonadism include loss of libido, PHYSIOLOGY OF OPIOID-ENDOCRINE infertility, fatigue, depression, anxiety, loss of muscle strength and INTERACTIONS mass, osteoporosis, and compression fractures in both men and The hypothalamic-pituitary-gonadal axis, which con- women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids trols the production of the primary sex hormones, for chronic pain, it has become increasingly important to monitor testosterone (androgen) and estradiol (estrogen), begins patients taking opioids and manage endocrine complications. with the secretion by the hypothalamus of gonadotropin Therefore, patients on opioid therapy should be routinely screened releasing hormone (GnRH) (Fig. 1). GnRH stimulates the for such symptoms and for laboratory abnormalities in sex pituitary gland to secrete luteinizing hormone (LH) and hormones. follicle stimulating hormone (FSH). These 2 hormones are Conclusions: Opioid-induced hypogonadism seems to be a common released into the systemic circulation and stimulate the complication of therapeutic or illicit opioid use. Patients on long- gonads—the testes and ovaries—to secrete testosterone or term opioid therapy should be prospectively monitored, and in estradiol, respectively. It should also be noted that estradiol cases of opioid-induced hypogonadism, we recommend nonopioid is also secreted by the testes through the aromatization of pain management, opioid rotation, or sex hormone supplementa- testosterone1 and that testosterone is secreted by the tion after careful consideration of the risks and benefits. ovarian theca cells.2 These sex hormones then exert a negative feedback on the hypothalamus and pituitary to Key Words: opioid, pain, hypogonadism, hormones, testosterone control the secretion of GnRH, LH, and FSH. Testosterone (Clin J Pain 2009;25:170–175) and estrogen support normal sexual and reproductive development and behavior. The hypothalamic-pituitary-gonadal axis is modulated by a complex series of outside influences as well. Opioids ‘‘(Opium) has kept, and does now keep down the population: are one of a number of such influences. Evidence suggests the women have fewer children than those of other that opioids, both endogenous and exogenous, can bind to countriesythe feeble opium-smokers of Assamyare more opioid receptors primarily in the hypothalamus, but effeminate than women.’’ potentially also in the pituitary and the testis, to modulate 3–8 Charles Alexander Bruce, ‘‘Report on the manufacture of tea gonadal function. Opioids have been shown to decrease and on the extent and produce of the tea plantations in the release of GnRH or interfere with its normal pulsatility Assam.’’ Calcutta, 1839. at the level of the hypothalamus, resulting in a decreased release of LH and FSH from the pituitary and a secondary fall in gonadal steroid production, that is, hypogonadism. Direct effects of opioids on the testis, including decreased pioids have been used for medicinal and analgesic secretion of testosterone and testicular interstitial fluid, Opurposes for millennia, and today remain a critical have also been documented.9 Opioid receptors have also part of the medical armamentarium against pain, diarrhea, been localized in ovarian tissue cultures and opioids have cough, and other symptoms. Unfortunately, although been shown to directly suppress ovarian steroid production in vitro.10 Opioids have been shown to increase pituitary 11 Received for publication March 25, 2008; revised June 26, 2008; release of prolactin in preclinical studies, which, in turn, accepted June 28, 2008. decreases testosterone secretion, although (as indicated From the *Analgesic Research, Tufts University School of Medicine; below) prolactin secretion is generally not affected in and wDepartment of Endocrinology, Diabetes and Nutrition, clinical studies. Lastly, opioids have also been shown to Boston University Medical Center, Boston, MA. Reprints: Nathanial Katz, MD, MS, Analgesic Research, 109 Highland alter the adrenal production of dehydroepiandrosterone Avenue, Needham, MA 02494 (e-mail: [email protected]). (DHEA), an important precursor of both testosterone in Copyright r 2009 by Lippincott Williams & Wilkins men and estradiol production in women.12 170 Clin J Pain Volume 25, Number 2, February 2009 Clin J Pain Volume 25, Number 2, February 2009 Opioids on the Endocrine System 9,22–27 TABLE 1. Endocrine Effects of Opioids lamic dysfunction. One of these studies showed that testosterone levels had returned to normal 1 month after Central hypogonadism (also called secondary or hypogonadotropic cessation of heroin use, suggesting that the effect of opioids hypogonadism) on the endocrine system is reversible.27 Several studies in Decreased hypothalamic GnRH Decreased pituitary LH, possibly FSH methadone-maintained male patients have shown decreased Decreased adrenal DHEAS and testosterone testosterone and LH levels consistent with central hypogo- 26 Decreased estradiol and progesterone (women) nadism. One of these studies showed a dose-response effect, Decreased testicular testosterone (men) in that patients on ‘‘low dose’’ methadone (10 to 60 mg/d) Possible cortisol deficiency had no evidence of testosterone level suppression, whereas Possible growth hormone deficiency (men) patients on ‘‘high dose’’ (80 to 150 mg/d) did. Another study9 demonstrated a peripheral effect on the testicle, with Effects apply to both men and women unless otherwise noted. DHEAS indicates dehydroepiandrosterone sulfate; FSH, follicle stimu- decreased secretion of testosterone and testicular interstitial lating hormone; GnRH, gonadotropin releasing hormone; LH, luteinizing fluid, and decreased sperm motility. One case series described hormone. amenorrhea and galactorrhea in female heroin addicts.28 Another study29 compared the endocrine function of 17 men treated with buprenorphine for addiction, 37 treated ENDOCRINE CONSEQUENCES OF OPIOID USE with high-dose methadone, and 51 healthy controls. Patients treated with buprenorphine had a significantly higher Opioid-induced Hypogonadism in Animals testosterone and a significantly lower frequency of sexual Investigations in animals have shown acute and 13 dysfunction compared with patients treated with methadone. chronic effects of opioids on the endocrine system, The testosterone level of buprenorphine-treated patients did including a decrease in testosterone levels via central not differ from that of healthy controls. This is the first study reductions of LH release (decreased hypothalamic release suggesting that not all opioids may be alike in terms of of LH releasing hormone leading to reduced pituitary endocrine effects in man, although it is not clear that release of LH), and peripheral effects on the testicle as 14–19 equivalent doses of methadone and buprenorphine were well. However, not all opioids have the same effect on compared in this study. testosterone levels: in rats, tramadol did not affect plasma testosterone levels and buprenorphine did not affect brain Opioid-induced Hypogonadism in Patients With testosterone levels, whereas other opioids tested (morphine Chronic Pain on Opioid Therapy 20 and fentanyl) affected both. Tramadol and buprenorphine In the pain arena, several studies of patients under- may not produce as much opioid hypogonadism as other going intrathecal opioid use for nonmalignant pain, compounds because they are not pure m agonists and have compared with patients with a comparable pain syndrome other properties: tramadol inhibits monoamine reuptake not on opioid therapy, have documented hypogonadism and buprenorphine is a partial m agonist with potential k 21 associated with low LH values and normal or low FSH antagonist features. levels in both men and women.29–34 These laboratory findings, which indicate hypogonadotropic hypogonadism, Opioid-induced Hypogonadism in were associated with decreased libido (men and women), Opioid-addicted Patients and in Patients impotence in men, and irregular or absent menses (oligor- Treated for Addiction rhea or amenorrhea) in women. Symptoms were reported to Studies in heroin addicts have demonstrated
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