The increasing use of glucagon-like peptide-1 (GLP-1) receptor agonists, such as Mounjaro (tirzepatide) by Eli Lilly and Company and Ozempic (semaglutide) by Novo Nordisk, for managing type 2 diabetes and obesity has spurred significant interest in their broader physiological effects. While these drugs are widely celebrated for improving blood sugar regulation and aiding weight loss, their potential influence on male fertility remains an area of concern and limited investigation.
GLP-1 receptor agonists function by mimicking the action of GLP-1, a hormone integral to regulating blood sugar levels and appetite. These drugs enhance insulin secretion, slow gastric emptying, and promote feelings of fullness, all well-documented mechanisms (Shaefer et al., 2015; Drucker, 2018). However, recent studies suggest that GLP-1 receptors are also found in male reproductive tissues, such as the testes, raising questions about the long-term impact of these drugs on male fertility (Jeibmann et al., 2005; Alves et al., 2016; Rago et al., 2020).
The relationship between metabolic health and reproductive function is well-documented, with conditions like obesity and diabetes often linked to decreased sperm quality and male infertility (Cabler et al., 2010; Du Plessis et al., 2010; Service et al., 2023). GLP-1 receptor agonists, by improving metabolic health, could theoretically lead to better reproductive outcomes. However, previous studies on GLP-1 agonists such as liraglutide have yielded mixed results. The direct effects of these medications on sperm function, hormone levels, and male fertility remain largely unexplored in clinical settings.
A search of the PubMed database in August 2024 identified 50 articles published between 2011 and 2024 on GLP-1 and fertility. Of these, only 16 articles focused on male fertility, either in human subjects or animal models. Studies in mice fed a high-fat diet revealed that while GLP-1 receptor agonists did not restore serum testosterone levels, they did improve sperm motility, mitochondrial function, and reduce sperm DNA fragmentation (Zhang et al., 2015). Other research has suggested that GLP-1 receptor activation could influence testicular function and spermatogenesis (Jensterle et al., 2019).
In human trials, liraglutide has shown promising effects on male fertility. One study indicated a significant increase in serum testosterone levels and improvements in sperm count, motility, and morphology (La Vignera et al., 2023). A randomized, double-blind trial found that men who experienced initial weight loss maintained a reduction in oligozoospermia (low sperm count) over a year (Andersen et al., 2022). Additionally, a study on healthy men undergoing four weeks of dulaglutide treatment reported no negative effects on sexual desire, hormone levels, or sperm parameters (Lengsfeld et al., 2024).
However, not all findings are positive. One study reported that liraglutide had a negative impact on sperm quality, which only returned to normal after five months of discontinuation, although the sperm count, motility, and semen volume did not fully return to baseline levels (Fontoura et al., 2014). Another study suggested that GLP-1 signaling could suppress testosterone production and negatively affect sperm quality (Jeibmann et al., 2005).
Given the crucial importance of fertility preservation for men of reproductive age, further investigation is essential to understand the long-term effects of GLP-1 receptor agonists on male reproductive health. Gametogenesis, the process of sperm cell development, spans approximately three months, making it highly sensitive to biological variations. Even small changes could significantly impact fertility. This underlines the need for dedicated clinical studies focusing on parameters like sperm count, motility, morphology, and hormone levels in men undergoing GLP-1 therapy. The effects may vary depending on dosage, treatment duration, and the presence of underlying health conditions.
In conclusion, while GLP-1 receptor agonists offer significant therapeutic benefits for managing metabolic conditions like type 2 diabetes and obesity, their potential effects on male fertility should not be overlooked. As these drugs are increasingly prescribed, it is vital to better understand their implications for reproductive health. Future clinical trials should prioritize this issue, ensuring that the long-term fertility outcomes are carefully considered, especially in men undergoing long-term treatment for chronic conditions. It is essential that the potential for long-term harm does not outweigh the temporary benefits of these drugs, as in some cases, the treatment may be more damaging than beneficial.
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