Diminished androgen levels are a common but often overlooked consequence of chronic opioid therapy. Although chronic pain is frequently manageable with chronic opioid therapy alone or combined with other medications, clinicians should be aware of the potential fallout from reduced androgen in patients that otherwise would not be expected to encounter this problem. Opioid-induced androgen deficiency, also known as opioid associated androgen deficiency (OPIAD), is one of the less commonly known side effects of opioids that affect both genders, especially men. Deficiency of the sex hormones can affect patients in very significant ways with potential decrease in quality of life and life expectancy.
To understand this particular side effect, we will first discuss how testosterone is controlled in the body in men, since the problem, although potentially problematic in women, occurs less frequently. The hypothalamic-pituitary-testosterone axis controls the amount of testosterone circulating in the body. It starts in the hypothalamus which secretes gonadotropin-releasing hormone (GnRH), GnRH then travels to the anterior pituitary. The anterior pituitary releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH travels down to the leydig cells in the testes and stimulates the production and secretion of testosterone while FSH travels to the sertoli cells to stimulate the production of sperm. The testosterone then has an inhibitory effect on the hypothalamus and the anterior pituitary through a negative feedback loop to decrease the amount of GnRH, LH, and FSH in the body. Here is a link for a visual reference of this hypothalamic-pituitary-testosterone axis.
Opioids, such as morphine (i.e. MS Contin®) and hydromorphone (i.e. Dilaudid®), bind to opioid receptors in the hypothalamus and inhibit the release of GnRH, which decreases the amount of LH and FSH released by the anterior pituitary, therefore decreasing the amount of testosterone released by the leydig cells in the testes. Men experience decreased testosterone levels as they age in general, but long term opioid use can decrease testosterone levels significantly in male patients at any age. Female patients are also at an increased risk of androgen deficiency and may experience similar symptoms as male patients. Some symptoms of associated hypoandrogenemia (low androgen levels) include: reduced libido, sexual dysfunction, decreased spontaneous erections, breast discomfort, loss of body/facial hair, hypogonadism, low sperm count, reduced bone mineral density, hot flushes and sweats. There are also cognitive symptoms such as decreased energy, motivation, and self-confidence and sleep disturbances. These symptoms listed and others are available in table form at this link. Not only can these symptoms decrease the quality of life, but the decreased hormone levels have been linked to other chronic disease states such as osteoporosis, metabolic syndrome and sleep apnea. The resultant outcome can be associated with decreased life expectancy. Particularly worth noting is that DEXA scans to determine bone density are not routinely ordered in patients that are not otherwise predetermined to be at risk for osteoporosis, perhaps the most common example is postmenopausal women. Imagine then the inherent jeopardy one might face if treated with chronic opioid therapy for a chronic spinal pain that is now more fragile from hormone-induced osteoporosis-the incidence of fracture.
Female patients can experience low estrogen and testosterone levels with prolonged opioid use, reaching approximately 50% lower levels than normal. They experience similar effects as male patients, with sexual dysfunction, reduced bone mineral density, dysmenorrhea, amenorrhea, and depression. Postmenopausal women experience lower LH and FSH levels compared to premenopausal women, although they decrease in both populations. The effects of the decreased hormone levels are not clear and more research is needed to determine the effects diminished androgen levels in women, and the possible risks and benefits of estrogen replacement therapy. For more information, please refer to Opioid Endocrinopathy in Women Consuming Prescribed Sustained Action Opioids for Control of Nonmalignant-Pain and Opioid Complications and Side Effects.
The treatment for opioid induced androgen deficiency in male patients is pharmacologically similar to hypogonadism, by use of testosterone replacement therapy. Formulations include oral (traditional, buccal), topical (transdermal patches, gels), implants, and depot injections. Preferred formulations are most often selected by patient preference, insurability, or both. Medscape has a nice review of these formulations, Options in Testosterone Replacement Therapy.
Intramuscular injections have been available for a while and they tend to be used frequently due to its first tier status on most insurance formularies, but the injections can be painful and can cause fluctuating serum testosterone levels. The fluctuating testosterone levels can cause side effects such as fluid retention, gynecomastia, and abnormal lipid levels. The implants are available in pellets that are transplanted subcutaneously in the flank area. These pellets dissolve over 4 to 6 months and deliver a steady amount of testosterone systemically. The pellets can cause infection, discomfort and pellet extrusion from the site of transplant, but they do offer convenience of infrequent dosing. The topical gel formulations are a very popular option if the patient can afford them. Gels reach steady state within 24 hours after application which decreases the likelihood of side effects such as mood swings. The patient needs to avoid physical contact with children or females after application and cannot shower or swim for 3 hours immediately following application. The buccal formulation is an option, but it can be displaced from the gum easily and cause gum irritation. The Endocrine Society Clinical Practice Guidelines contain summary tables of the various available testosterone formulations. The side effects of testosterone replacement therapy include: acne, oily skin, breast tenderness, gynecomastia, fluid retention, increased RBC, and low sperm count.
Not all pain medications affect the hypothalamus-pituitary-androgen axis the same way. For example, Bliesener and colleagues* showed in one study that the partial opioid agonist buprenorphine was compared to methadone in terms of their effects on testosterone. Patients who were taking buprenorphine had higher plasma testosterone levels when compared to those taking methadone for pain management. Female patients were also observed to have less androgen-based side effects with buprenorphine. This information and other Opioid Complications and Side Effects are nicely reviewed in the indicated link. Buprenorphine is also discussed in the Endocrine Society Clinical Practice Guidelines noted above.
* Bliesener N, Albrecht S, Schwager A,Weckbecker K, Lichtermann D, Klingmuller D. Plasma testosterone and sexual function in men receiving buprenorphine
Take home points:
- Opioids can cause opioid induced androgen deficiency by binding to the opioid receptors on the hypothalamus and inhibiting the secretion of gonadotropin releasing hormone (GnRH).
- This can cause decreased testosterone levels in both males and females.
- The common side effects are: reduced libido, sexual dysfunction, decreased spontaneous erections, breast discomfort, loss of body/facial hair, hypogonadism, low sperm count, low bone mineral density (leading to osteopenia and eventual osteoporosis).
- Female patients may experience amenorrhea or irregular menstruation from a low serum level of estrogen and testosterone.
- Treatment for opioid induced androgen deficiency is testosterone replacement therapy.
- The different formulations include injection, implants, topical, buccal, and oral.
- The side effects include: acne, oily skin, breast tenderness, gynecomastia, fluid retention, increased RBC, and low sperm count.
- Buprenorphine does not affect androgen levels as much as other opioids.
Clinicians should always make a point to ask about energy levels, sleep patterns, and check for physical and behavioral signs of opioid-induced androgen deficiency. Normalizing hormone levels from opioid-induced reductions can affect and extend a patient’s quality of life.
Biosketch: Natsuki Kubotera (Suki) is a Pharm.D. Intern at
Albany College of Pharmacy & Health Sciences, PY4.
She has a bachelor’s degree in psychology with a minor in French
from SUNY Oswego. When she is not practicing for her pharmacy career,
Suki enjoys rock climbing, traveling, hiking, and eating delicious cupcakes.