Pain Medications and Male Reproduction

Abstract

The increasing use of opioid medications has become a crisis in developed countries. The profound negative effects of opioids on male reproduction are well known, but this topic is absent from the current conversations about these medications. In the fertility clinic, a significant proportion of our patients are using opioids for pain management, and the options for these men are unclear. Opioids exert their negative effects by a variety of mechanisms. At high doses, testosterone levels fall significantly and hypogonadism is seen. In part, this results from increased prolactin and inhibition of gonadotropin production/secretion by the pituitary. However, negative effects on the testis are seen even in the absence of decreased androgen levels. As we review in this chapter, Leydig and germ cells produce endogenous opioids, and receptors for these substances are present throughout the testis. For example, endogenous opioids produced by Leydig and germ cells provide paracrine inhibition at Sertoli cell receptors, decreasing the production of androgen binding protein, which is required for intra-testis transport of androgens. Morphine also increases the expression of aromatase in the brain and testis and acts directly on the testis and germ cells to decrease testicular function. Exogenous opioids in men reduce semen quality, including increased DNA fragmentation. All opioids have these effects, but less damage is caused by lower doses, shorter-acting opioids, and by some drugs with mixed receptor activity, such as tramadol and tapentadol. The non-steroid anti-inflammatory drugs (NSAIDS) have much less effect on the male reproductive system, although there is a paucity of human studies. Paracetamol has been shown to cause sperm abnormalities, including DNA fragmentation, and to increase time to pregnancy and may prove to be of greater concern. In rodents, paracetamol has negative impacts on seminiferous tubule histology and fertility. Robust, well-designed studies in humans are needed.

Differential Regulation of Gonadotropins as Revealed by Transcriptomes of Distinct LH and FSH Cells of Fish Pituitary

“…The Delta opioid receptor ( dop ) is enriched in LH cells in males (Log2(fold change) = 1.9). Opioids regulate pain, behavior, and appetite, and are considered to have negative effects on LH secretion in mammals [ 110 , 111 ]. In fish on the other hand, opioid action on LH secretion can be contradicting and was suspected to affect the hypothalamic control of LH secretion.…”

Mechanisms of Central Hypogonadism

“…The negative effects of opiates are legion, and their effects on male reproduction are well known [ 93 ]. However, there seems to be a general lack of awareness among healthcare professionals regarding the potential for CH in male users of opiates, and this discussion is often absent during clinically-based treatments with opiate therapies, including those discussions with patients [ 93 ]. In a recent systematic review and meta-analysis of opiate effects on the HPG axis, de Vries and colleagues identified 52 studies from the literature, with >18,400 subjects [ 94 ].…”

<p>Tapentadol: an overview of the safety profile</p>

“…Opioid-induced androgen deficiency (OPIAD) is commonly reported in association with opioid therapy 41,42. Noteworthy, it has been suggested that drugs characterized by dual activity, such as tapentadol, may be associated with a more favorable pattern of endocrine-related toxicity 42.…”

“…Opioid-induced androgen deficiency (OPIAD) is commonly reported in association with opioid therapy 41,42. Noteworthy, it has been suggested that drugs characterized by dual activity, such as tapentadol, may be associated with a more favorable pattern of endocrine-related toxicity 42. Eichenbaum et al evaluated the effects of tapentadol in healthy male volunteers versus placebo and morphine and in patients with osteoarthritis, compared with placebo and oxycodone 41.…”