Opioids have been used for centuries in the treatment of conditions such as chronic pain, diarrhea, cough, and other symptoms. However, it is only within the last century that physicians observed the negative effects on hormonal balance from long-term opioid use; these effects are also not common knowledge. Opioids have been shown to decrease libido, cause menstrual irregularities and even induce infertility. Awareness of these side effects becomes more important as opioids are increasingly used as therapeutic options for pain management.
How are hormones affected by opioids?
The gonadal hormones of testosterone and estrogen are controlled via the hypothalamic-pituitary-gonadal axis. The hypothalamus secretes gonadotropin-releasing hormone (GNRH), which in turn stimulates the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH and FSH enter the circulatory system, and stimulate cells in the testes or ovaries to secrete either testosterone or estrogen, respectively. The elevated levels of the sex hormones provide feedback to the hypothalamus and pituitary, lowering secretion via a negative feedback loop. Testosterone and estrogen are important to maintaining normal sexual and reproductive functions.
Evidence collected through the years suggests that opioids bind to opioid receptors in the hypothalamus and affect gonadal function. Opioid receptors have also been found in the pituitary and testes. Exogenous and endogenous opioids have been shown to interfere with the release of GNRH by the hypothalamus, thus decreasing the pituitary release of FSH and LH. Direct effects of opioids on these have been demonstrated, particularly a reduction in testosterone released and testicular interstitial fluid. The release of prolactin, on the other hand, appears to be stimulated by opioids, and can provide a secondary mechanism of decreasing testosterone secretion.
What are the effects of decreased hormones?
Studies have demonstrated that long-term exposure to opioids results in a hypogonadic state, which presents with symptoms of gonad insufficiency. This can present as the loss of libido and impotence in males. This is often accompanied by anxiety, depression and reductions in overall quality of life. In females receiving long-term opioid therapy, menstrual irregularities and infertility have been observed. Decreased cortisol levels eventually lead to Addisonian crisis in some patients. In some cases, it was observed that patients who presented with hypogonadism also had significantly increased sensitivity to pain.
While these symptoms have been observed in long-term users of opioid drugs, there is evidence that suggests that the negative effects of opioids may not all be equally potent. For example, it has been observed that patients being treated with buprenorphine had significantly higher levels of testosterone and lower levels of sexual dysfunction when compared to patients treated with methadone.
How is hormone dysfunction diagnosed?
Diagnosis of hormone dysfunction secondary to long-term opioid use is made after a complete medical history and physical examination by the physician. In particular, questions will focus on the signs and symptoms related to hypogonadism, including decreased libido, fatigue, decreased muscle mass, absent or irregular menses, etc. There are no standard clinical examinations to arrive at a diagnosis, although ancillary requests for serum levels of FSH and LH may be requested to provide evidence of hypogonadism.
How is hypogonadism secondary to opioid therapy managed?
The medical literature on hypogonadism from long-term opioid use is relatively scarce, and the comprehensive guidelines on the diagnosis and management of these cases are yet to be developed. Therefore, the treatment plan will depend largely upon clinical assessment and physician judgment of patient response to the various therapeutic options available.
Conservative management may initially be attempted. As opioids are central to the management of pain symptoms, particularly for chronic pain, totally removing opioids may not be an acceptable option. The varying negative effects of the different kinds of opioids suggest that rotation of opioid drugs can be a viable option to alleviate hormone dysfunction.
However, if the symptoms persist despite attempts to rotate opioids, then testosterone supplementation may be considered. A commonly used threshold for testosterone supplementation therapy is serum concentration <600 ng/dL.
What are the options for opioid therapy?
Numerous options have been developed for testosterone replacement therapy. Preparations such as intramuscular injections, transdermal patches and transdermal gels have been used. During this time, monitoring of patient response to therapy and testosterone levels may be initiated.