Opioid Endocrinopathy
The most studied effect of opioids on the endocrine system is their suppression of the male gonadal axis; decreased testosterone levels have been termed opioid-induced androgen deficiency (OPIAD). Opioids decrease pulsatile secretion of gonadotropin-releasing hormone, leading to the development of hypogonadotropic hypogonadism; however, other mechanisms have also been hypothesized such as increased sex hormone-binding globulin production, which decreases available free testosterone. In rats, morphine injection increased aromatase and 5α-reductase mRNA expression, increasing the conversion of testosterone to estradiol and dihydrotestosterone, respectively, possibly lowering levels of testosterone. Mu-opioid receptors are also found on human spermatozoa, and incubation with morphine led to a decrease in sperm motility, which was reversed by naloxone. This study demonstrated a direct effect of opioids on fertility.
Different modes of opioid administration have been studied, including intrathecal, oral, and transdermal, with all resulting in decreased serum testosterone concentrations and symptoms of hypogonadism. Ninety-six percent of males receiving intrathecal morphine developed symptoms including loss of libido; 86% of patients had testosterone levels below the lower limit of normal <259 ng/dL compared to only 9% of controls. Serum luteinizing hormone (LH) levels were also significantly lower in the opioid group, with 69% of male opioid patients having an LH below the reference range. LH appears to be more significantly decreased in males on opioid therapy compared to follicle-stimulating hormone (FSH). Another study reported similar results: males receiving intrathecal morphine had lower testosterone, LH, and FSH levels with decreased libido compared to controls. Oral opioids similarly decrease testosterone levels. Daniell reported in a cross-sectional study that chronic oral opioid administration decreased total and free testosterone in a dose-dependent manner, with the lowest testosterone levels in patients consuming the highest opioid dose. Males in the highest quartile of sustained-action opioids (in morphine equivalents) had an average total testosterone level of 172.1 ng/dL compared to 449.1 ng/dL in controls (P<.0001). Patients on chronic methadone maintenance treatment (MMT) for heroin addiction also have lower testosterone levels compared to age-matched controls (16,17). Females may also develop hypogonadism. Abs et al showed that 69% of females had decreased or no libido after initiating intrathecal opioids. All 21 premenopausal females developed amenorrhea or irregular menstrual cycles after intrathecal opioid therapy. Premenopausal females on oral opioids had significant decreases in estradiol and LH levels compared to controls (56.6 pg/mL vs. 138.9 pg/mL, P<.05) but minimal differences in FSH levels. This study also reported that these females had irregular menstrual cycles (87%) and sexual dysfunction (83%). Serum dehydroepiandrosterone-sulfate (DHEA-S) levels were low in females who chronically took opioids (51.2 mcg/dL vs. 113.3 mcg/dL, P<.01), as were testosterone and estradiol levels, suggesting that opioid use suppresses both gonadal and adrenal function. Menopause before age 50 was found in 52% of opioid users compared to 20% of controls. Most (92%) opioid-consuming females complained of fatigue, decreased libido, depression, and decreased sexual satisfaction.
Despite the relatively small number of studies, some conclusions can be made. The prevalence of hypogonadism appears to be high among opioid users, with 75 to 100% of opioid consumers studied with symptoms and/or chemical evidence of hypogonadism. Hypogonadism occurs with decreased LH/FSH levels in both males and females as early as 1 week after starting opioid therapy, with LH levels more affected in males. OPIAD also appears to be dose dependent; lower levels of testosterone are measured in subjects who take progressively higher doses of opioids. Different opioid preparations also affect the axis to differing degrees. Limited information is available regarding the effects of partial mu-receptor agonist opioids such as tramadol and buprenorphine. Tramadol, a weak mu-receptor agonist, also has effects on serotonin and norepinephrine release similar to selective norepinephrine reuptake inhibitors; but it is metabolized to a stronger mu-receptor agonist. Buprenorphine is a partial mu-receptor agonist that may have less effect on the HPG axis compared to classic opioids. In a cross-sectional study, buprenorphine treated patients had higher testosterone levels (5.1 ng/mL vs. 2.8 ng/mL, P<.0001) and less sexual dysfunction than methadone-treated patients (23% vs. 83%, P<.0001). Buprenorphine may thus be an alternative to classic mu-opioid receptor agonist by causing fewer OPIAD symptoms. OPIAD may improve with opioid discontinuation, indicating that the effects are reversible, but the time course of gonadal function restoration has not been determined.
Relatively little is known about OPIAD from different opioid doses or administration routes. It is unknown whether there is threshold for developing hypogonadal symptoms. There are no comparisons among different opioids to determine if a particular mu-receptor agonist is more likely induces OPIAD. Chronic hypogonadism has been postulated to cause metabolic syndrome, diabetes, and hypertension. Conversely, obesity and diabetes are associated with secondary hypogonadism. Hypogonadism from androgen deprivation therapy is associated with increased cardiovascular disease, and this effect may also be similar in OPIAD. Treatment with testosterone was found to decrease the mortality rate of males with type 2 diabetes to that of the control group. It is unclear if OPIAD itself leads to metabolic derangements with lasting negative impacts on health. The roles of underlying disorders, obesity, and changes in body composition with inactivity need to be determined; hence, it is important to determine if hormone replacement prevents or ameliorates consequences of hypogonadism, including effects on bone, cardiovascular risk, and depression.
While opioid cessation would likely be the most effective treatment for OPIAD, hormone replacement may prevent the long-term consequences of hypogonadism. Testosterone replacement is commonly used for male hypogonadism to improve libido and sense of well-being and to maintain bone mineral density (BMD). Treatment of hypogonadism with testosterone gel replacement significantly improves pain ratings and depression scale scores in OPIAD patients. Pain levels and quality of life should be evaluated before and after initiating testosterone replacement in patients with OPIAD.
Clomiphene, a selective estrogen receptor modulator (estrogen agonist/antagonist), has been used to increase testosterone levels in males without negatively impacting fertility. Clomiphene blocks the feedback inhibition of estradiol at the hypothalamus, causing increased LH and FSH release, thus stimulating Leydig and Sertoli cells to produce testosterone and spermatozoa, respectively. Oral clomiphene increased testosterone levels similar to topical testosterone gel (573 ng/mL vs. 553 ng/mL) in a prospective trial but was much less expensive ($83/month vs. $265/month). Clomiphene may be an alternative to testosterone replacement to treat functional hypogonadism, but clinical trials are needed in OPIAD patients.
Hypothalamic-Pituitary-Gonadal Axis
The most studied effect of opioids on the endocrine system is their suppression of the male gonadal axis; decreased testosterone levels have been termed opioid-induced androgen deficiency (OPIAD). Opioids decrease pulsatile secretion of gonadotropin-releasing hormone, leading to the development of hypogonadotropic hypogonadism; however, other mechanisms have also been hypothesized such as increased sex hormone-binding globulin production, which decreases available free testosterone. In rats, morphine injection increased aromatase and 5α-reductase mRNA expression, increasing the conversion of testosterone to estradiol and dihydrotestosterone, respectively, possibly lowering levels of testosterone. Mu-opioid receptors are also found on human spermatozoa, and incubation with morphine led to a decrease in sperm motility, which was reversed by naloxone. This study demonstrated a direct effect of opioids on fertility.
Different modes of opioid administration have been studied, including intrathecal, oral, and transdermal, with all resulting in decreased serum testosterone concentrations and symptoms of hypogonadism. Ninety-six percent of males receiving intrathecal morphine developed symptoms including loss of libido; 86% of patients had testosterone levels below the lower limit of normal <259 ng/dL compared to only 9% of controls. Serum luteinizing hormone (LH) levels were also significantly lower in the opioid group, with 69% of male opioid patients having an LH below the reference range. LH appears to be more significantly decreased in males on opioid therapy compared to follicle-stimulating hormone (FSH). Another study reported similar results: males receiving intrathecal morphine had lower testosterone, LH, and FSH levels with decreased libido compared to controls. Oral opioids similarly decrease testosterone levels. Daniell reported in a cross-sectional study that chronic oral opioid administration decreased total and free testosterone in a dose-dependent manner, with the lowest testosterone levels in patients consuming the highest opioid dose. Males in the highest quartile of sustained-action opioids (in morphine equivalents) had an average total testosterone level of 172.1 ng/dL compared to 449.1 ng/dL in controls (P<.0001). Patients on chronic methadone maintenance treatment (MMT) for heroin addiction also have lower testosterone levels compared to age-matched controls (16,17). Females may also develop hypogonadism. Abs et al showed that 69% of females had decreased or no libido after initiating intrathecal opioids. All 21 premenopausal females developed amenorrhea or irregular menstrual cycles after intrathecal opioid therapy. Premenopausal females on oral opioids had significant decreases in estradiol and LH levels compared to controls (56.6 pg/mL vs. 138.9 pg/mL, P<.05) but minimal differences in FSH levels. This study also reported that these females had irregular menstrual cycles (87%) and sexual dysfunction (83%). Serum dehydroepiandrosterone-sulfate (DHEA-S) levels were low in females who chronically took opioids (51.2 mcg/dL vs. 113.3 mcg/dL, P<.01), as were testosterone and estradiol levels, suggesting that opioid use suppresses both gonadal and adrenal function. Menopause before age 50 was found in 52% of opioid users compared to 20% of controls. Most (92%) opioid-consuming females complained of fatigue, decreased libido, depression, and decreased sexual satisfaction.
Despite the relatively small number of studies, some conclusions can be made. The prevalence of hypogonadism appears to be high among opioid users, with 75 to 100% of opioid consumers studied with symptoms and/or chemical evidence of hypogonadism. Hypogonadism occurs with decreased LH/FSH levels in both males and females as early as 1 week after starting opioid therapy, with LH levels more affected in males. OPIAD also appears to be dose dependent; lower levels of testosterone are measured in subjects who take progressively higher doses of opioids. Different opioid preparations also affect the axis to differing degrees. Limited information is available regarding the effects of partial mu-receptor agonist opioids such as tramadol and buprenorphine. Tramadol, a weak mu-receptor agonist, also has effects on serotonin and norepinephrine release similar to selective norepinephrine reuptake inhibitors; but it is metabolized to a stronger mu-receptor agonist. Buprenorphine is a partial mu-receptor agonist that may have less effect on the HPG axis compared to classic opioids. In a cross-sectional study, buprenorphine treated patients had higher testosterone levels (5.1 ng/mL vs. 2.8 ng/mL, P<.0001) and less sexual dysfunction than methadone-treated patients (23% vs. 83%, P<.0001). Buprenorphine may thus be an alternative to classic mu-opioid receptor agonist by causing fewer OPIAD symptoms. OPIAD may improve with opioid discontinuation, indicating that the effects are reversible, but the time course of gonadal function restoration has not been determined.
Relatively little is known about OPIAD from different opioid doses or administration routes. It is unknown whether there is threshold for developing hypogonadal symptoms. There are no comparisons among different opioids to determine if a particular mu-receptor agonist is more likely induces OPIAD. Chronic hypogonadism has been postulated to cause metabolic syndrome, diabetes, and hypertension. Conversely, obesity and diabetes are associated with secondary hypogonadism. Hypogonadism from androgen deprivation therapy is associated with increased cardiovascular disease, and this effect may also be similar in OPIAD. Treatment with testosterone was found to decrease the mortality rate of males with type 2 diabetes to that of the control group. It is unclear if OPIAD itself leads to metabolic derangements with lasting negative impacts on health. The roles of underlying disorders, obesity, and changes in body composition with inactivity need to be determined; hence, it is important to determine if hormone replacement prevents or ameliorates consequences of hypogonadism, including effects on bone, cardiovascular risk, and depression.
While opioid cessation would likely be the most effective treatment for OPIAD, hormone replacement may prevent the long-term consequences of hypogonadism. Testosterone replacement is commonly used for male hypogonadism to improve libido and sense of well-being and to maintain bone mineral density (BMD). Treatment of hypogonadism with testosterone gel replacement significantly improves pain ratings and depression scale scores in OPIAD patients. Pain levels and quality of life should be evaluated before and after initiating testosterone replacement in patients with OPIAD.
Clomiphene, a selective estrogen receptor modulator (estrogen agonist/antagonist), has been used to increase testosterone levels in males without negatively impacting fertility. Clomiphene blocks the feedback inhibition of estradiol at the hypothalamus, causing increased LH and FSH release, thus stimulating Leydig and Sertoli cells to produce testosterone and spermatozoa, respectively. Oral clomiphene increased testosterone levels similar to topical testosterone gel (573 ng/mL vs. 553 ng/mL) in a prospective trial but was much less expensive ($83/month vs. $265/month). Clomiphene may be an alternative to testosterone replacement to treat functional hypogonadism, but clinical trials are needed in OPIAD patients.
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