JBRA Assist. Reprod. 2024;28(2):331-340
REVIEW
doi: 10.5935/1518-0557.20240020
Effects of major analgesics on male fertility: A systematic literature review
1Christus University Center (UNICHRISTUS), Biomedicine Department. Fortaleza-Ceará, Brazil
The work was carried out at Christus University Center (UNICHRISTUS).
CONFLICT OF INTEREST
The authors declare no conflicts of interest
ABSTRACT
Objective: To verify, based on a systematic literature review, the effects of the main analgesics on male fertility.
Data Sources: The studies were analyzed from the PubMed, SciELO and LILACS databases.
Study Selection: The articles selected for the present review included: cohort studies; cross-sectional studies, clinical trials; complete studies; studies with animal models that addressed the proposed theme and that were published within the stipulated period from March 1, 2013, to March 31, 2023, in English, Portuguese and Spanish. These would later have to go through inclusion stages such as framing the type of study and exclusion criteria.
Data Collection: Author’s name, year of publication, study population, number of patients, analgesic, administration time, dose, and effect.
Conclusions: There are in vitro and in vivo studies that link paracetamol and ibuprofen to endocrine and seminal changes that are harmful to male fertility. However, more clinical research is needed to determine the doses and timing of administration that affect fertility. The effects of aspirin on male fertility are still unclear due to the lack of studies and consistent methodologies. There is not enough research on dipyrone and its relationship with male fertility, requiring more studies in this area.
Keywords: male infertility, hormonal changes, NSAIDs, sperm quality, human reproduction
INTRODUCTION
Analgesics, broadly classified as opioids and non-opioids, encompass a diverse group of pain-relieving medications. The non-opioid category is notably heterogeneous, comprising subgroups such as non-steroidal anti-inflammatory drugs (NSAIDs), antipyretics, and other analgesics (Schneider et al., 2019). Due to its diverse nature, some medications within this class, despite long-standing use, have not had their mechanism of action and side effects completely elucidated, as is the case with paracetamol (PCM) (Castel-Branco et al., 2013). Nevertheless, this class of medications represents the most widely consumed globally, given its application in the management of mild to moderate pain and its availability without a prescription (McCrae et al., 2018).
In Brazil, analgesics stand as the most commonly used medications, as indicated by a study conducted by Borges et al. (2023). Among these, paracetamol, dipyrone, and aspirin rank as the most frequently utilized. Although ibuprofen was not explicitly mentioned in this category, it was grouped with anti-inflammatories like naproxen and diclofenac sodium. PCM, owing to its analgesic and antipyretic effects, enjoys widespread use on a global scale (Ennis et al., 2016). Its consumption is advocated for the treatment of acute and chronic pain, as well as for fever management. Furthermore, its use has been proposed in the closure of the ductus arteriosus in premature infants (Bührer et al., 2021). Its pharmacological properties mirror those of NSAIDs, suppressing prostaglandin production through the inhibition of cyclooxygenase (COX) enzymes, namely COX-1 and COX-2 (Jóźwiak-Bebenista & Nowak, 2014; Przybyła et al., 2021).
Dipyrone, also known as metamizole, stands as the most widely used analgesic in Brazil and is available over the counter in various forms. This medication possesses antipyretic, antispasmodic, analgesic, and anti-inflammatory properties (Knappmann & Melo, 2010). However, it is important to note that dipyrone can induce adverse effects, most notably agranulocytosis, leading to its discontinuation in several countries, including the United States, Canada, Denmark, and the United Kingdom (de Leeuw et al., 2017; Nikolova et al., 2012; Siramshetty et al., 2016). Although its mechanism of action has been extensively studied, it remains not fully understood. It is established that the metabolites 4-N-methylaminoantipyrine and amino antipyrine inhibit prostaglandin production, and its analgesic effect stems from the inhibition of COX enzymes, primarily COX-2 (Pereira, 2014; Rogosch et al., 2012).
One of the earliest synthesized drugs was aspirin (AAS), a notable representative of non-steroidal anti-inflammatory drugs (NSAIDs), and since its inception, it has held a prominent position as one of the most widely used analgesics. Moreover, it remains unparalleled as the most prevalent drug in the modern era (Fijałkowski et al., 2022). Its continued global consumption can be attributed to its diverse applications in the medical field, encompassing analgesic and antipyretic properties (Fuster & Sweeny, 2011). However, its antiplatelet characteristic is a key driver of its extensive use for preventing cardiovascular and cerebrovascular diseases (Montinari et al., 2019). The primary mechanism of action of AAS involves irreversible inhibition of COX-1, COX-2, and COX-3, achieved through the inhibition of prostaglandin precursors and thromboxane production (Sankaranarayanan et al., 2020; Ornelas et al., 2017).
Another crucial medication is Ibuprofen, belonging to the NSAIDs group and widely available in pharmacies worldwide. Primarily administered orally, it exhibits antipyretic, anti-inflammatory, and analgesic properties (Irvine et al., 2018). As commonly known, NSAIDs act through the inhibition of COX enzymes that metabolize arachidonic acid, resulting in reduced prostaglandin synthesis (Fitzgerald & Patrono, 2001). Ibuprofen acts on both COX-1 and COX-2, inhibiting prostaglandins and related compounds located peripherally (Atkinson et al., 2015). However, high doses of ibuprofen administration can lead to undesirable adverse effects such as heartburn, gastritis, epigastric pain, and kidney damage, with potential long-term consequences like renal papillary necrosis, peptic ulcers, and gastrointestinal bleeding (Moriarty & Carroll, 2016; Irvine et al., 2018).
Therefore, as previously mentioned regarding ibuprofen, all medications carry adverse effects. NSAIDs are known to induce severe side effects, notably impacting the gastrointestinal, renal, and cardiovascular systems (Arfè et al., 2016; Ziya Şener & Okşul, 2020; Dreischulte et al., 2015; Essex et al., 2013). High doses of paracetamol (PCM) have been correlated with hepatotoxicity, kidney and heart problems, and reproductive system toxicity in some studies (Uysal et al., 2016; Murad et al., 2016; Turtle et al., 2013; Aksu et al., 2016). Indiscriminate use of dipyrone can lead to severe adversities such as agranulocytosis, interstitial nephritis, alveolitis, pneumonitis, hepatitis, aplastic anemia, Stevens-Johnson syndrome, and toxic epidermal necrosis (Garcez et al., 2018; Silva et al., 2015).
Moreover, studies have demonstrated that the use of analgesics by adult men can impact testosterone synthesis in the body, resulting in decreased concentration, reduction in germ cell numbers, and induction of oxidative stress, leading to apoptosis of spermatocytes. All these factors can contribute to male infertility (Hurtado-Gonzalez et al., 2018; Konkel, 2018).
According to a recent World Health Organization (WHO) report (2023), approximately 1 in 6 individuals (17.5%) globally experience challenges in conceiving. Another significant observation is that infertility affects around 15-20% of reproductive-age couples, with approximately 85% of cases having an identifiable cause, while the cause remains unknown in 15% of cases (Sihag et al., 2018; Carson & Kallen, 2021). The male factor can contribute up to 60% to a couple’s infertility but is solely responsible in 20% of cases (Patel et al., 2017).
Male infertility is a complex syndrome encompassing various disorders and can result from anatomical, genetic, systemic, neurological, infectious, and immunological factors, among others. Despite advances in understanding male infertility, approximately 50% of cases remain idiopathic, lacking an apparent cause (Poongothai et al., 2009).
In recent years, exposure to chemicals and drugs has been associated with male infertility. Agarwal et al. (2021) delineated key aspects of male infertility, including primary screening tests, diagnosis, causes, and risk factors. They highlighted exposure to gonad toxicants, including certain medications such as painkillers, chemotherapy drugs, radiotherapy treatments, and contact with pesticides and heavy metals, as factors that should be considered during infertility evaluation. This exposure has been linked to reduced sperm levels in some cases.
In the literature, there is a growing discussion regarding the potential harmful effects on fertility from the prolonged use of non-opioid analgesics. Hence, this study was conceived to establish a correlation between the use of major analgesics and male infertility.
MATERIALS AND METHODS
Study Type
This study represents a systematic literature review conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement, 2022) guideline, ensuring comprehensive and rigorous review methodology (Moher et al., 2009).
Search Strategy
To conduct the searches in this study, Medical Subjects Headings (MeSH) were initially reviewed to identify appropriate descriptors. Subsequently, these descriptors were combined using Boolean operators to formulate four distinct searches: (1) Male infertility OR Semen Quality AND Aspirin, (2) Male infertility OR Semen Quality AND Ibuprofen, (3) Male infertility OR Semen Quality AND Acetaminophen, (4) Male infertility OR Semen Quality AND Dipyrone. These search strategies were implemented across three databases: PubMed, SciELO, and LILACS.
Study Eligibility Criteria
The studies evaluated in this review were those published between June 2013 and March 2023, and they were considered regardless of the language of publication, encompassing articles in English, Portuguese, and Spanish.
Criteria for Selecting Studies
Inclusion Criteria
• In selecting studies for this review, the following eligibility criteria were adopted:
• Cohort studies
• Cross-sectional studies
• Clinical trials
• Complete studies
• Studies with animal models
• Studies that specifically addressed the theme proposed by the authors
Exclusion Criteria
The following criteria were used to exclude studies:Studies falling outside the scope of the research
Review articles
Letters to the editor
Case reports
Duplicate articles
Incomplete articles
Unavailable articles
Data Collection
Following the execution of the searches, the articles underwent evaluation based on their title and abstract. Those that did not meet the specified criteria were excluded from further consideration. Articles that aligned with the predetermined review criteria were then evaluated by a panel of three authors (M.C.F., M.B.A., and M.G.A.). In cases where unanimous agreement was reached regarding the clinical outcome, the relevant data were tabulated. However, in instances of any discrepancies, a fourth specialist author in the field (M.P.B.) conducted a re-analysis.
Data Extraction
Upon completing the initial selection process, the chosen articles were carefully reviewed to extract the following data:
• Author’s name
• Year of publication
• Study population
• Number of patients
• Analgesic used
• Administration time
• Dose
• Effect on male fertility
RESULTS
The initial data search yielded a total of 140 articles across PubMed (n=53), SciELO (n=87), and LILACS (n=0). Following the removal of duplicate articles (n=10), 130 unique articles remained for screening. After a thorough review of titles and abstracts, 112 articles that did not meet the inclusion criteria were excluded, leaving 18 articles for full reading. After a comprehensive review of these 18 articles, 9 were selected for detailed analysis (Figure 1).
Figure 1. Methodological Screening.
Effects of Paracetamol on Male Fertility
Among the 9 selected articles, four investigated the correlation between sperm quality and the use of paracetamol, as summarized in Table 1. Two of these studies utilized C57BL/6 mice, one involved 468 male participants, and one utilized testicular cells for the tests (Albert et al., 2013; Holm et al., 2015; Smarr et al., 2017; Ma et al., 2018).
Table 1. Changes in male fertility caused by analgesics.
In animal model studies, particularly with C57BL/6 mice, a reduction in testosterone secretion, anogenital distance, sperm motility and density, spermatid density, an increase in pregnenolone levels, oxidative stress, and the number of dead sperm were observed (Holm et al., 2015; Ma et al., 2018). Another study using testicular cell culture plates demonstrated a decrease in testosterone levels accompanied by a reduction in prostaglandins E2 (PGE2) and prostaglandins D2 (PGD2) (Albert et al., 2013). Additionally, a study involving 468 male patients of reproductive age revealed an association between an increase in urinary paracetamol concentration and a reduction in sperm volume, sperm motility, morphometry, and a slight increase in DNA fragmentation (Smarr et al., 2017).
Effects of Ibuprofen on Male Fertility
Three of the articles investigated the association between ibuprofen and male fertility. Two of these studies were conducted using animal models, involving adult NMRI mice and Wistar rats, respectively, while the third study used human cells from 12 men with normal spermatogenesis.
In the study of Roodbari et al. (2015) three groups of 12 adult NMRI mice each were utilized, with divisions into a control group, a normal dosage group of 30 mg/kg, and a high dosage group of 57 mg/kg. The study observed a reduction in sperm quality in animals treated with ibuprofen. The study by Barbosa et al. (2020) used Wistar rats to examine the effects of ibuprofen on the male reproductive system. A total of 48 animals were equally divided into a control group and three experimental groups receiving different doses of ibuprofen (2.4 mg/kg, 7.2 mg/kg, and 14.3 mg/kg). This research demonstrated a reduction in normal sperm, alterations in sperm tail morphology, decreased motile sperm, reduced daily sperm production, and a decrease in sperm located in the epididymis across all doses of ibuprofen administered in Wistar rats.
In an analysis utilizing human testicular peritubular cells to investigate the effects of ibuprofen, tests were conducted with the drug and prostaglandin E2 (PGE2) in serum-free media for 24 hours. The concentration of ibuprofen used was based on the levels of this analgesic found in the blood of the 12 patients. The tests correlated the use of ibuprofen with a reduction in prostaglandin E2 levels, glial cell line-derived neurotrophic factor (GDNF) levels, and mRNA concentrations (Rey-Ares et al., 2018).
Effects of Aspirin on Male Fertility
Two articles were included in this review to investigate the impact of aspirin (acetylsalicylic acid - ASS) on male fertility. The study by Banihani & Shatnawi (2020) utilized seminal samples from 43 healthy and fertile men. These samples were categorized into three groups: the first exposed to aspirin at a concentration of 0.1mM, the second at 1mM, and the third serving as the control group. Following aliquot preparation, they were incubated for an hour at 37°C, and subsequently examined. The analysis of motility revealed a reduction in both aspirin-exposed groups. Specifically, the group with the highest aspirin concentration exhibited a 43.5% reduction in motility, while the group with the lowest concentration displayed a 16.6% reduction compared to the control group. Sample vitality was also assessed, demonstrating a 16.01% reduction in group 1 and a 3.63% reduction in group 2 relative to the control group. Additionally, two other compounds were quantified in the samples: calcium and nitrite. Both exhibited a reduction, though the reduction in nitrite levels did not reach statistical significance.
In the study of Martins et al. (2021), conducted on Wistar rats, the effects of aspirin (AAS) and dipyrone on seminal quality were examined. The aspirin group comprised 7 rats, administered a dose of 100 mg/kg of the drug over a 15-day period. Animals treated with aspirin showed a nearly 60% reduction in testosterone levels, a 56.58% decrease in daily sperm production, and a 56.64% reduction in the number of spermatids when compared to the control group.
Effects of Dipyrone on Male Fertility
A singular study concerning the adverse effects of dipyrone on male fertility was identified. Martins et al. (2021) adopted a methodology similar to the tests conducted with aspirin (AAS). Animals subjected to this medication exhibited a 60% reduction in testosterone levels, a 55.04% decrease in daily sperm production, and a 54.42% reduction in the number of spermatids compared to the control group.
DISCUSSION
Infertility afflicts more than 180 million individuals globally, with male factors solely contributing to 20% of cases and playing a significant role in 50% of couples’ infertility (Esteves et al., 2021). Male infertility stems from diverse causes, ranging from genetic mutations and diseases to lifestyle choices and medication use. Indeed, the administration of analgesics has been associated with risks that can adversely affect reproduction in animals (Agarwal et al., 2020; Ratnasooriya & Jayakody, 2000; Høyer et al., 2017). Epidemiological studies have revealed that exposure to paracetamol (PCM), either alone or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), during the first and second trimesters of pregnancy is linked to a higher rate of cryptorchidism (Berkowitz & Lapinski, 1996; Kristensen et al., 2016; Stukenborg et al., 2021). Jensen et al. (2010) and Kristensen et al. (2011a) were able to associate the use of analgesics with the incidence of cryptorchidism in newborns. Consequently, literature has suggested that PCM causes endocrine dysregulation and may interfere with the endocrine system in humans, affecting prostaglandin synthesis and testosterone production in men (Wiger et al., 1995; Axelstad et al., 2018; Kristensen et al., 2011b).
In the study conducted by Mazaud-Guittot et al. (2013), the impact of paracetamol, aspirin, and indomethacin on endocrine disruptions in the human fetal testis was investigated, with potential interference in the process of testicular descent. The study explored gene expression and hormone production involved in testicular development in cultures of human fetal testis cells exposed to these drugs. Results demonstrated that paracetamol led to a decrease in testosterone production, while aspirin and indomethacin stimulated its production. All three drugs also caused a decrease in prostaglandin E2 (PGE2) levels in the testicles. Thus, this study highlights that analgesics can induce endocrine disturbances in the human fetal testicle, affecting hormone production and potentially interfering with testicular descent. The approach employed in this study allows for the investigation of the direct effects of these drugs on testicular cells, offering an initial understanding of potential mechanisms involved. However, it is important to acknowledge that full replication of the conditions and complexities of the in vivo environment is not possible, limiting the generalizability of the results to living humans. These findings align with the articles analyzed in the present study, all of which observed a negative correlation between the use of PCM and hormone production.
Albert et al. (2013) conducted a study utilizing testicular cells to investigate the effect of paracetamol (PCM) on hormonal levels. Their results demonstrated that PCM possesses the capability to disrupt the production of testosterone in Leydig cells. This reduction in hormone secretion directly impacts seminal quality. Additionally, the study observed that the analgesic exhibits antagonistic activity in the production of prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequently, Holm et al. (2015) conducted an in vivo study using C57BL/6JBomTac lineage mice. One of the primary objectives was to investigate the connection between exposure to aniline and PCM in the womb and potential effects on the development of the male reproductive system. After histological and endocrine evaluations, it was observed that intrauterine exposure to paracetamol in relevant pharmaceutical doses led to a decrease in testosterone secretion. Furthermore, it resulted in a shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels. In humans, this marker is associated with reproductive malformations and reproductive disorders in adulthood.
The subsequent year, Holm et al. (2015) replicated the study from the previous year, this time analyzing the effects of PCM and aniline on the female reproductive system. The study unveiled that intrauterine exposure is linked to adverse effects on the reproductive development of females. These chemical substances induced alterations in the growth of primary and secondary follicles, consequently decreasing follicle reserves. These structures are vital for egg production and the normal functioning of ovaries. Furthermore, it was observed that exposure could compromise fertility, affecting the ability to conceive and reproduce. Hence, based on these studies, it is plausible to assume that the use of PCM during pregnancy may pose a significant risk to the reproductive health of the offspring, irrespective of gender.
Hormonal alterations were also evidenced in the in vivo study conducted by van den Driesche et al. (2015). In this study, two tests were performed: firstly, a xenograft model utilized human fetal testicular tissue in mice to evaluate the effects of administering recommended doses of paracetamol (PCM) for seven days. The results indicated a significant decrease in testosterone levels in the plasma and seminal vesicle weight. Subsequently, they evaluated the impact of intrauterine exposure to PCM on male fertility, revealing that PCM leads to a reduction in testosterone levels by interfering with the expression of critical steroidogenic enzymes. These findings affirm the anti-gonadotropic effect of the studied analgesic on men. Nevertheless, further research endeavors aim to correlate the use of analgesics, such as PCM, with seminal quality issues.
Since 1990, studies have endeavored to establish a relationship between PCM usage, seminal quality, and its effects on male fertility. However, the findings have presented discrepancies (Gandy et al., 1990; Ratnasooriya & Jayakody, 2000; Ekaluo et al., 2009; Aksu et al., 2016). Notably, two articles identified in this review provided evidence supporting the deleterious effects of this medication on seminal quality (Smarr et al., 2017; Ma et al., 2018). Particularly, the study by Smarr et al. (2017), which analyzed 468 men, revealed that participants with elevated urinary PCM levels exhibited alterations in motility, morphology, DNA fragmentation levels, and an increased time to pregnancy. Furthermore, Rossitto et al. (2019) demonstrated, through an in utero study with rats, the repercussions of using PCM and ibuprofen during pregnancy. Male offspring exposed to these medications exhibited a 19% reduction in sperm count in semen. The second generation also displayed a 40% reduction in motility when both parents were exposed. Thus, once again, studies underscore the relationship between PCM usage and male fertility. However, comprehensive human studies are imperative to provide a more nuanced understanding.
In contrast to PCM, where research has confirmed its endocrine-disrupting activity in the developing male fetus and its impact on adult male fertility, studies focusing on nonsteroidal anti-inflammatory drugs (NSAIDs) remain inconclusive due to the dearth of research in humans (Drobnis & Nangia, 2017). This class of medications ranks among the most widely used globally, and numerous studies in recent decades have investigated their effects when administered during pregnancy and adulthood (Dean & Sharpe, 2013; Lind et al., 2017; Uzun et al., 2015; Bagoji et al., 2017). In this review, four studies examining the effects of ibuprofen were identified, and their results are consistent, revealing the potential of this class to induce detrimental effects on male fertility (Roodbari et al., 2015; Rey-Ares et al., 2018; Barbosa et al., 2020). The study by Roodbari et al. (2015) observed alterations in seminal quality parameters, such as reduced viability, sperm quantity, motility, and decreased chromatin integrity. These findings align with the results reported by Barbosa et al. (2020), who also administered ibuprofen in an animal model. In addition to these similar effects, they noted a reduction in the number of sperm in the epididymis and daily production. Another study aimed to evaluate the deleterious effects on spermatogenesis while demonstrating the potential role of selenium in mitigating testicular toxicity induced by ibuprofen. It was observed that the administration of these NSAIDs to rats resulted in decreased volume, global count, and motility. These changes were correlated with an increase in testicular reactive oxygen species (Sharma et al., 2020).
Moreover, the impact of ibuprofen use during pregnancy was investigated by Ben Maamar et al. (2017), revealing that this analgesic can alter the growth of the male fetal testicle in humans, potentially affecting male reproductive capabilities. In summary, existing literature primarily comprises in vivo studies demonstrating that this anti-inflammatory agent can diminish sperm quality, with documented reductions in motility, viability, sperm count, and DNA integrity (Stutz et al., 2000; Robinson et al., 2005; Ingram et al., 2006; Rocco et al., 2012).
Despite the substantial research on the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on male fertility, scant research is available in databases analyzing the impacts of acetylsalicylic acid (ASA) on seminal quality. Hence, only three articles were uncovered in this review that correlate the use of the drug with its anti-androgenic properties and detrimental effects on male fertility (Albert et al., 2013; Banihani & Shatnawi, 2020; Martins et al., 2021). Exposure to ASA in human renal cortex cells at concentrations of 0.01 and 0.1mM resulted in a notable reduction in testosterone levels of approximately 18% and 17%, respectively, over 24 hours, and approximately 14% and 12%, respectively, over 48 hours (Albert et al., 2013). Additionally, a study employing rat fetal testes concluded that aspirin exerts specific and direct antiandrogenic effects (Kristensen et al., 2012). In a study conducted in India in 2018, an in vivo analysis utilizing rats found that aspirin usage over one to two months led to a reduction in motility, density, and total quantity of sperm in the semen (Vyas et al., 2016). Furthermore, assessments with 43 human seminal samples indicated reduced motility and vitality following exposure to ASA at concentrations of 0.1 and 1.0mM for one hour (Banihani & Shatnawi, 2020). Consequently, there is a consensus among researchers that ASA has an adverse impact on semen quality parameters.
In humans, cyclooxygenase (COX) inhibitors such as ASA, PCM, or ibuprofen have been associated with compromised sperm quality. Nonetheless, in-depth investigations regarding the effects of dipyrone on the male reproductive system and the involvement of the epididymis in the fertility-impeding effects of COX inhibitors are warranted (Drobnis & Nangia, 2017; Kristensen et al., 2012; Sadeghzadeh et al., 2019). Moreover, there is a paucity of studies in the existing literature concerning this topic, largely due to the prohibition of the sale and medical use of this medication in key research-centric countries such as the United Kingdom, Canada, and the United States owing to its adverse effects (de Leeuw et al., 2017; Nikolova et al., 2012; Siramshetty et al., 2016).
The sole article identified in our research reported that the daily administration of 100 mg/kg of dipyrone for 15 days in Wistar rats resulted in decreased sperm production, sperm count in the epididymis, and serum testosterone levels (Martins et al., 2021). However, the precise mechanism underlying the reduction of testosterone levels in the body induced by non-opioid analgesics and NSAIDs remains uncertain. Consequently, a study conducted in Brazil combined in vivo and in vitro tests to scrutinize the effects of dipyrone on steroidogenesis and its potential receptor-mediated anti-androgenic effects. The findings revealed a reduction in testosterone production, attributed to the inhibition of enzymes at various stages of steroidogenesis. Nonetheless, it was concluded that dipyrone did not exert an anti-androgenic effect on the body (Passoni et al., 2018).
CONCLUSION
The literature emphasizes the detrimental effects of paracetamol and ibuprofen on male fertility, substantiated by comprehensive in vitro and in vivo investigations. However, a significant gap exists in clinical research, warranting further exploration into optimal administration timing and dosage. The impact of aspirin and dipyrone on male fertility remains ambiguous due to a scarcity of studies and disparate methodologies employed. Adequate in vitro and in vivo research is imperative to comprehensively understand the effects of aspirin. Moreover, the dearth of studies exploring the influence of dipyrone on male fertility poses a challenge in establishing a concrete correlation, underscoring the necessity for additional research in this domain.
List of Abbreviations
Aspirin (AAS)
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Cyclooxygenase (COX)
Paracetamol (PCM)
Prostaglandin D2 (PGD2)
Prostaglandin E2 (PGE2)
REFERENCES
Agarwal A, Baskaran S, Parekh N, Cho CL, Henkel R, Vij S, Arafa M, Panner Selvam MK, Shah R. Male infertility. Lancet. 2021;397:319-33. PMID: 33308486 DOI: 10.1016/S0140-6736(20)32667-2. Medline
Aksu EH, Özkaraca M, Kandemir FM, Ömür AD, Eldutar E, Küçükler S, Çomaklı S. Mitigation of paracetamol-induced reproductive damage by chrysin in male rats via reducing oxidative stress. Andrologia. 2016;48:1145-54. DOI: 10.1111/and.12553. PMID: 26914515. Medline
Albert O, Desdoits-Lethimonier C, Lesné L, Legrand A, Guillé F, Bensalah K, Dejucq-Rainsford N, Jégou B. Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum Reprod. 2013;28:1890-8. PMID: 23670170 DOI: 10.1093/humrep/det112. Medline
Arfè A, Scotti L, Varas-Lorenzo C, Nicotra F, Zambon A, Kollhorst B, Schink T, Garbe E, Herings R, Straatman H, Schade R, Villa M, Lucchi S, Valkhoff V, Romio S, Thiessard F, Schuemie M, Pariente A, Sturkenboom M, Corrao G; Safety of Non-steroidal Anti-inflammatory Drugs (SOS) Project Consortium. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ. 2016;354:i4857. PMID: 27682515 DOI: 10.1136/bmj.i4857. Medline
Atkinson HC, Stanescu I, Frampton C, Salem II, Beasley CP, Robson R. Pharmacokinetics and Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral Administration. Clin Drug Investig. 2015;35:625-32. PMID: 26334726 DOI: 10.1007/s40261-015-0320-8. Medline
Axelstad M, Hass U, Scholze M, Christiansen S, Kortenkamp A, Boberg J. EDC IMPACT: Reduced sperm counts in rats exposed to human relevant mixtures of endocrine disrupters. Endocr Connect. 2018;7:139-48. PMID: 29203468. DOI: 10.1530/EC-17-0307. Medline
Bagoji IB, Hadimani GA, Yendigeri SM, Das KK. Sub-chronic indomethacin treatment and its effect on the male reproductive system of albino rats: possible protective role of black tea extract. J Basic Clin Physiol Pharmacol. 2017;28:201-7. PMID: 28222030. DOI: 10.1515/jbcpp-2016-0168. Medline
Banihani SA, Shatnawi RM. Aspirin decreases human sperm motility and vitality, chelates seminal calcium, but insignificantly reduces seminal nitric oxide production. Andrologia. 2020;52:e13776. PMID: 32725931. DOI: 10.1111/and.13776. Medline
Barbosa MG, Jorge BC, Stein J, Santos Ferreira DA, Barreto ACDS, Reis ACC, Moreira SDS, Inocencio LCL, Macorini LFB, Arena AC. Pre-pubertal exposure to ibuprofen impairs sperm parameters in male adult rats and compromises the next generation. J Toxicol Environ Health A. 2020;83:559-72. PMID: 32615883. DOI: 10.1080/15287394.2020.1786483. Medline
Ben Maamar M, Lesné L, Hennig K, Desdoits-Lethimonier C, Kilcoyne KR, Coiffec I, Rolland AD, Chevrier C, Kristensen DM, Lavoué V, Antignac JP, Le Bizec B, Dejucq-Rainsford N, Mitchell RT, Mazaud-Guittot S, Jégou B. Ibuprofen results in alterations of human fetal testis development. Sci Rep. 2017;7:44184. PMID: 28281692. DOI: 10.1038/srep44184. Medline
Berkowitz GS, Lapinski RH. Risk factors for cryptorchidism: a nested case-control study. Paediatr Perinat Epidemiol. 1996;10:39-51. PMID: 8746430. DOI: 10.1111/j.1365-3016.1996.tb00024.x. Medline
Bührer C, Endesfelder S, Scheuer T, Schmitz T. Paracetamol (Acetaminophen) and the Developing Brain. Int J Mol Sci. 2021;22:11156. PMID: 34681816. DOI: 10.3390/ijms222011156. Medline
Carson SA, Kallen AN. Diagnosis and Management of Infertility: A Review. JAMA. 2021;326:65-76. PMID: 34228062. DOI: 10.1001/jama.2021.4788. Medline
de Leeuw TG, Dirckx M, Gonzalez Candel A, Scoones GP, Huygen FJPM, de Wildt SN. The use of dipyrone (metamizol) as an analgesic in children: What is the evidence? A review. Paediatr Anaesth. 2017;27:1193-201. PMID: 29024184. DOI: 10.1111/pan.13257. Medline
Dean A, Sharpe RM. Clinical review: Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab. 2013;98:2230-8. PMID: 23569219. DOI: 10.1210/jc.2012-4057. Medline
Dreischulte T, Morales DR, Bell S, Guthrie B. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney Int. 2015;88:396-403. PMID: 25874600. DOI: 10.1038/ki.2015.101. Medline
Drobnis EZ, Nangia AK. Pain Medications and Male Reproduction. Adv Exp Med Biol. 2017;1034:39-57. PMID: 29256126. DOI: 10.1007/978-3-319-69535-8_6. Medline
Ennis ZN, Dideriksen D, Vaegter HB, Handberg G, Pottegård A. Acetaminophen for Chronic Pain: A Systematic Review on Efficacy. Basic Clin Pharmacol Toxicol. 2016;118:184-9. PMID: 26572078. DOI: 10.1111/bcpt.12527. Medline
Essex MN, Zhang RY, Berger MF, Upadhyay S, Park PW. Safety of celecoxib compared with placebo and non-selective NSAIDs: cumulative meta-analysis of 89 randomized controlled trials. Expert Opin Drug Saf. 2013;12:465-77. PMID: 23506230. DOI: 10.1517/14740338.2013.780595. Medline
Esteves SC, Zini A, Coward RM, Evenson DP, Gosálvez J, Lewis SEM, Sharma R, Humaidan P. Sperm DNA fragmentation testing: Summary evidence and clinical practice recommendations. Andrologia. 2021;53:e13874. PMID: 33108829. DOI: 10.1111/and.13874. Medline
Fijałkowski Ł, Skubiszewska M, Grześk G, Koech FK, Nowaczyk A. Acetylsalicylic Acid-Primus Inter Pares in Pharmacology. Molecules. 2022;27:8412. PMID: 36500502. DOI: 10.3390/molecules27238412. Medline
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:433-42. PMID: 11496855. DOI: 10.1056/NEJM200108093450607. Medline
Fuster V, Sweeny JM. Aspirin: a historical and contemporary therapeutic overview. Circulation. 2011;123:768-78. PMID: 21343593. DOI: 10.1161/CIRCULATIONAHA.110.963843. Medline
Gandy J, Millner GC, Bates HK, Casciano DA, Harbison RD. Effects of selected chemicals on the glutathione status in the male reproductive system of rats. J Toxicol Environ Health. 1990;29:45-57. PMID: 2299686. DOI: 10.1080/15287399009531370. Medline
Holm JB, Chalmey C, Modick H, Jensen LS, Dierkes G, Weiss T, Jensen BA, Nørregård MM, Borkowski K, Styrishave B, Martin Koch H, Mazaud-Guittot S, Jegou B, Kristiansen K, Kristensen DM. Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development. Toxicol Sci. 2015;148:288-98. PMID: 26259604. DOI: 10.1093/toxsci/kfv179. Medline
Høyer BB, Ramlau-Hansen CH, Bonde JP, Larsen SB, Toft G. Use of non-prescription analgesics and male reproductive function. Reprod Toxicol. 2017;74:70-6. PMID: 28899770. DOI: 10.1016/j.reprotox.2017.09.004. Medline
Hurtado-Gonzalez P, Anderson RA, Macdonald J, van den Driesche S, Kilcoyne K, Jørgensen A, McKinnell C, Macpherson S, Sharpe RM, Mitchell RT. Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems. Environ Health Perspect. 2018;126:047006. PMID: 29665328. DOI: 10.1289/EHP2307. Medline
Ingram MJ, Zeller E, Moss GP, Hall CE. A potential anti-implantation and spermicidal strategy: putative derivatives of nonoxynol-9 and anti-inflammatory agents and their spermicidal activity. Eur J Contracept Reprod Health Care. 2006;11:258-61. PMID: 17484190. DOI: 10.1080/13625180600907487. Medline
Irvine J, Afrose A, Islam N. Formulation and delivery strategies of ibuprofen: challenges and opportunities. Drug Dev Ind Pharm. 2018;44:173-83.PMID: 29022772. DOI: 10.1080/03639045.2017.1391838. Medline
Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sørensen HT, Bonde JP, Henriksen TB, Olsen J. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology. 2010;21:779-85. PMID: 20805751. DOI: 10.1097/EDE.0b013e3181f20bed. Medline
Jóźwiak-Bebenista M, Nowak JZ. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm. 2014;71:11-23. PMID: 24779190. Medline
Knappmann AL, Melo EB. Quality of over-the-counter medicines: a study with dipyrone brands commercialized in a drugstore in Cascavel city (Paraná, Brazil). Cienc Saude Colet. 2010;15:3467-76. PMID: 21120334. DOI: 10.1590/S1413-81232010000900021. Medline
Konkel L. Uncomfortable Uncertainty: Do OTC Analgesics Disrupt Fetal Germ Cell Development? Environ Health Perspect. 2018;126:94001. PMID: 30230350. DOI: 10.1289/EHP3799. Medline
Kristensen DM, Hass U, Lesné L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jégou B, Leffers H. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod. 2011a;26:235-44. PMID: 21059752. DOI: 10.1093/humrep/deq323. Medline
Kristensen DM, Skalkam ML, Audouze K, Lesné L, Desdoits-Lethimonier C, Frederiksen H, Brunak S, Skakkebæk NE, Jégou B, Hansen JB, Junker S, Leffers H. Many putative endocrine disruptors inhibit prostaglandin synthesis. Environ Health Perspect. 2011b;119:534-41. PMID: 21081300. DOI: 10.1289/ehp.1002635. Medline
Kristensen DM, Lesné L, Le Fol V, Desdoits-Lethimonier C, Dejucq-Rainsford N, Leffers H, Jégou B. Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis. Int J Androl. 2012;35:377-84. PMID: 22612476. DOI: 10.1111/j.1365-2605.2012.01282.x. Medline
Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesné L, Serrano T, Main KM, Jégou B. Analgesic use - prevalence, biomonitoring and endocrine and reproductive effects. Nat Rev Endocrinol. 2016;12:381-93. PMID: 27150289. DOI: 10.1038/nrendo.2016.55. Medline
Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J, Andersen HR, Andersen MS, Skakkebæk NE, Jensen TK. Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs. Hum Reprod. 2017;32:223-31. PMID: 27852690. DOI: 10.1093/humrep/dew285. Medline
Ma Q, Shao H, Feng Y, Zhang L, Li P, Hu X, Ma Z, Lou H, Zeng X, Luo G. A new bioluminescent imaging technology for studying oxidative stress in the testis and its impacts on fertility. Free Radic Biol Med. 2018;124:51-60. PMID: 29803806. DOI: 10.1016/j.freeradbiomed.2018.05.080. Medline
Martins ABM, Bezerra MS, da Costa Gomes LT, Trajano FMG, Dantas PB, de Sena MO, Gavioli EC, da Silva Junior ED. Effects of dipyrone and acetylsalicylic acid on contractions of distal cauda epididymis duct, serum testosterone and sperm count in rats. Basic Clin Pharmacol Toxicol. 2021;129:183-95. PMID: 34196104. DOI: 10.1111/bcpt.13633. Medline
Mazaud-Guittot S, Nicolas Nicolaz C, Desdoits-Lethimonier C, Coiffec I, Ben Maamar M, Balaguer P, Kristensen DM, Chevrier C, Lavoué V, Poulain P, Dejucq-Rainsford N, Jégou B. Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent. J Clin Endocrinol Metab. 2013;98:E1757-67. PMID: 24030937. DOI: 10.1210/jc.2013-2531. Medline
McCrae JC, Morrison EE, MacIntyre IM, Dear JW, Webb DJ. Long-term adverse effects of paracetamol - a review. Br J Clin Pharmacol. 2018;84:2218-30. PMID: 29863746. DOI: 10.1111/bcp.13656. Medline
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. PMID: 19621072. DOI: 10.1371/journal.pmed.1000097. Medline
Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots - A concise summary. Vascul Pharmacol. 2019;113:1-8. PMID: 30391545. DOI: 10.1016/j.vph.2018.10.008. Medline
Moriarty C, Carroll W. Ibuprofen in paediatrics: pharmacology, prescribing and controversies. Arch Dis Child Educ Pract Ed. 2016;101:327-30. PMID: 27458064. DOI: 10.1136/archdischild-2014-307288. Medline
Murad HA, Habib H, Kamel Y, Alsayed S, Shakweer M, Elshal M. Thearubigins protect against acetaminophen-induced hepatic and renal injury in mice: biochemical, histopathological, immunohistochemical, and flow cytometry study. Drug Chem Toxicol. 2016;39:190-8. PMID: 26234406. DOI: 10.3109/01480545.2015.1070170. Medline
Ornelas A, Zacharias-Millward N, Menter DG, Davis JS, Lichtenberger L, Hawke D, Hawk E, Vilar E, Bhattacharya P, Millward S. Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev. 2017;36:289-303. PMID: 28762014. DOI: 10.1007/s10555-017-9675-z. Medline
Passoni MT, Kristensen MN, Morais RN, Woitkowiak C, Boareto AC, da Silva Amaral BA, Grechi N, Dalsenter PR, Munkboel CH, Styrishave B, Kristensen DM, Gomes C, van Ravenzwaay B, Martino-Andrade AJ. Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor. Toxicol Lett. 2018;285:139-47. PMID: 29289696. DOI: 10.1016/j.toxlet.2017.12.021. Medline
Patel AS, Leong JY, Ramasamy R. Prediction of male infertility by the World Health Organization laboratory manual for assessment of semen analysis: A systematic review. Arab J Urol. 2017;16:96-102. PMID: 29713540. DOI: 10.1016/j.aju.2017.10.005. Medline
Poongothai J, Gopenath TS, Manonayaki S. Genetics of human male infertility. Singapore Med J. 2009;50:336-47. PMID: 19421675. Medline
PRISMA statement. 2022. July 23, 2022. Available at: http://www.prisma-statement.org/
Przybyła GW, Szychowski KA, Gmiński J. Paracetamol - An old drug with new mechanisms of action. Clin Exp Pharmacol Physiol. 2021;48:3-19. PMID: 32767405. DOI: 10.1111/1440-1681.13392. Medline
Ratnasooriya WD, Jayakody JR. Long-term administration of large doses of paracetamol impairs the reproductive competence of male rats. Asian J Androl. 2000;2:247-55. PMID: 11202412. Medline
Rey-Ares V, Rossi SP, Dietrich KG, Köhn FM, Schwarzer JU, Welter H, Frungieri MB, Mayerhofer A. Prostaglandin E2 (PGE2) is a testicular peritubular cell-derived factor involved in human testicular homeostasis. Mol Cell Endocrinol. 2018;473:217-24. PMID: 29408603. DOI: 10.1016/j.mce.2018.01.022. Medline
Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo V, Nüsing R, Imming P. Novel bioactive metabolites of dipyrone (metamizol). Bioorg Med Chem. 2012;20:101-7. PMID: 22172309. DOI: 10.1016/j.bmc.2011.11.028. Medline
Roodbari F, Abedi N, Talebi AR. Early and late effects of Ibuprofen on mouse sperm parameters, chromatin condensation, and DNA integrity in mice. Iran J Reprod Med. 2015;13:703-10. PMID: 26730245. Medline
Rossitto M, Marchive C, Pruvost A, Sellem E, Ghettas A, Badiou S, Sutra T, Poulat F, Philibert P, Boizet-Bonhoure B. Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen. FASEB J. 2019;33:339-57. PMID: 29979629. DOI: 10.1096/fj.201800488RRR. Medline
Sadeghzadeh F, Mehranjani MS, Mahmoodi M. Vitamin C ameliorates the adverse effects of dexamethasone on sperm motility, testosterone level, and spermatogenesis indexes in mice. Hum Exp Toxicol. 2019;38:409-18. PMID: 30526067. DOI: 10.1177/0960327118816137. Medline
Sankaranarayanan R, Kumar DR, Altinoz MA, Bhat GJ. Mechanisms of Colorectal Cancer Prevention by Aspirin-A Literature Review and Perspective on the Role of COX-Dependent and -Independent Pathways. Int J Mol Sci. 2020;21:9018. PMID: 33260951. DOI: 10.3390/ijms21239018. Medline
Schneider J, Kreutz R, Bolbrinker J. Pharmacology of non-opioid analgesics. Schmerz. 2019;33:165-79. PMID: 30535850. DOI: 10.1007/s00482-018-0339-x. Medline
Sharma P, Kaur P, Ghanghas P, Kaur J, Kaushal N. Selenium Ameliorates Ibuprofen Induced Testicular Toxicity by Redox Regulation: Running Head: Se protects against NSAID induced testicular toxicity. Reprod Toxicol. 2020;96:349-58. PMID: 32800787. DOI: 10.1016/j.reprotox.2020.08.005. Medline
Sihag P, Tandon A, Pal R, Jain BK, Bhatt S, Kaur S, Sinha A. Sonography in male infertility: a look beyond the obvious. J Ultrasound. 2018;21:265-76. PMID: 29594932. DOI: 10.1007/s40477-018-0294-5. Medline
Siramshetty VB, Nickel J, Omieczynski C, Gohlke BO, Drwal MN, Preissner R. WITHDRAWN--a resource for withdrawn and discontinued drugs. Nucleic Acids Res. 2016;44:D1080-6. PMID: 26553801. DOI: 10.1093/nar/gkv1192. Medline
Smarr MM, Kannan K, Chen Z, Kim S, Buck Louis GM. Male urinary paracetamol and semen quality. Andrology. 2017;5:1082-8. PMID: 28853221. DOI: 10.1111/andr.12413. Medline
Stukenborg JB, Mitchell RT, Söder O. Endocrine disruptors and the male reproductive system. Best Pract Res Clin Endocrinol Metab. 2021;35:101567. PMID: 34426080. DOI: 10.1016/j.beem.2021.101567. Medline
Stutz G, Martini AC, Ruiz RD, Fiol De Cuneo M, Munoz L, Lacuara JL. Functional activity of mouse sperm was not affected by low doses of aspirin-like drugs. Arch Androl. 2000;44:117-28. PMID: 10746868. DOI: 10.1080/014850100262281. Medline
Turtle EJ, Dear JW, Webb DJ. A systematic review of the effect of paracetamol on blood pressure in hypertensive and non-hypertensive subjects. Br J Clin Pharmacol. 2013;75:1396-405. PMID: 23145789. DOI: 10.1111/bcp.12032. Medline
Uysal HB, Dağlı B, Yılmaz M, Kahyaoğlu F, Gökçimen A, Ömürlü İK, Demirci B. Biochemical and Histological Effects of Thiamine Pyrophosphate against Acetaminophen-Induced Hepatotoxicity. Basic Clin Pharmacol Toxicol. 2016;118:70-6. PMID: 26432613. DOI: 10.1111/bcpt.12496. Medline
Uzun B, Atli O, Perk BO, Burukoglu D, Ilgin S. Evaluation of the reproductive toxicity of naproxen sodium and meloxicam in male rats. Hum Exp Toxicol. 2015;34:415-29. PMID: 25034942. DOI: 10.1177/0960327114542886. Medline
van den Driesche S, Macdonald J, Anderson RA, Johnston ZC, Chetty T, Smith LB, Mckinnell C, Dean A, Homer NZ, Jorgensen A, Camacho-Moll ME, Sharpe RM, Mitchell RT. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model. Sci Transl Med. 2015;7:288ra80. PMID: 25995226. DOI: 10.1126/scitranslmed.aaa4097. Medline
Vyas A, Ram H, Purohit A, Jatwa R. Adverse Effects of Subchronic Dose of Aspirin on Reproductive Profile of Male Rats. J Pharm. 2016;2016:6585430. PMID:27190691. DOI: 10.1155/2016/6585430. Medline
Wiger R, Hongslo JK, Evenson DP, De Angelis P, Schwarze PE, Holme JA. Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice. Reprod Toxicol. 1995;9:21-33. PMID: 8520128. DOI: 10.1016/0890-6238(94)00052-x. Medline
Ziya Şener Y, Okşul M. Effects of NSAIDs on kidney functions and cardiovascular system. J Clin Hypertens. 2020;22:302. PMID: 31913564. DOI: 10.1111/jch.13769. Medline