Pregabalin Does Not Affect Sperm Production in Healthy Volunteers: A Randomized, Double‐blind, Placebo‐controlled, Noninferiority Study

Sikka, Suresh C.; Chen, Crystal; Almas, Mary; Dula, Eugene; Knapp, Lloyd

doi:10.1111/papr.12171

Cited by 11 publications

(6 citation statements)

References 12 publications

(19 reference statements)

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“…With regard to differences in the conclusions of the studies, the peer-reviewed reports for seven drugs were found to contradict the information present in the DailyMed labels. Four of the drugs had contradictory findings in human studies (pregabalin, colchicine, cortisone, and dexamethasone [ 14 , 24 , 25 , 27 , 28 ]), and one drug had contradictory findings in a study performed in rats (gabapentin [ 15 ]). The pro-drug for another agent (AZA, which is metabolized to 6-mercaptopurine) was reported to have no effects in humans or animals [ 36 , 37 ], and there was conflicting data in the literature regarding the effects of methotrexate in humans [ 40 , 41 ].…”

Section: Agreement Of the Peer-reviewed Literature With The Informatimentioning

confidence: 99%

“…Moreover, some of the findings included in the drug labels are difficult to interpret. For example, although the current drug label in DailyMed indicates that pregabalin leads to epididymitis, which can negatively impact sperm production, a study published in early 2015 concluded that pregabalin did not negatively impact sperm production in healthy volunteers [ 14 ]. It is therefore unclear whether the percentage of affected patients (reported to be ∼1% in the drug label) was too low to lead to a significant finding in the recent clinical trial, or whether the epididymitis in these patients was not associated with decreased spermatogenesis.…”

Section: Limitations Of This Review and Future Directionsmentioning

confidence: 99%

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FDA-approved medications that impair human spermatogenesis

et al. 2016

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We herein provide an overview of the single-ingredient U.S. Food and Drug Administration (FDA)-approved drugs that affect human spermatogenesis, potentially resulting in a negative impact on male fertility. To provide this information, we performed an in-depth search of DailyMed, the official website for FDA-approved drug labels. Not surprisingly, hormone-based agents were found to be the drugs most likely to affect human spermatogenesis. The next category of drugs most likely to have effects on spermatogenesis was the antineoplastic agents. Interestingly, the DailyMed labels indicated that several anti-inflammatory drugs affect spermatogenesis, which is not supported by the peer-reviewed literature. Overall, there were a total of 65 labels for drugs of various classes that showed that they have the potential to affect human sperm production and maturation. We identified several drugs indicated to be spermatotoxic in the drug labels that were not reported in the peer-reviewed literature. However, the details about the effects of these drugs on human spermatogenesis are largely lacking, the mechanisms are often unknown, and the clinical impact of many of the findings is currently unclear. Therefore, additional work is needed at both the basic research level and during clinical trials and post-marketing surveillance to fill the gaps in the current knowledge. The present findings will be of interest to physicians and pharmacists, researchers, and those involved in drug development and health care policy.

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Section: Agreement Of the Peer-reviewed Literature With The Informatimentioning

confidence: 99%

Section: Limitations Of This Review and Future Directionsmentioning

confidence: 99%

FDA-approved medications that impair human spermatogenesis

et al. 2016

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“…Not all of the studies included in our review used the most up to date edition of the WHO criteria available when conducting their trial. Studies defining semen analysis parameters using WHO 1992 criteria were commenced in 2012 and 2006 and could have utilized the WHO 1999 criteria when conducting the trial ( Selice et al , 2011 ; Sikka et al , 2015 ). A similar issue was identified with some studies defining semen analysis criteria using WHO 1999 , where the trial was commenced in 2013 or 2016 after the introduction of WHO 2010 ( Haje and Naoom, 2015 ; Hosseini et al , 2016 ; Tehrani et al , 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Outcome reporting across randomized controlled trials evaluating potential treatments for male infertility: a systematic review

Rimmer

Howie

Subramanian

et al. 2022

Human Reproduction Open

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STUDY QUESTION What are the primary outcomes and outcome measures used in randomized controlled trials (RCTs) evaluating potential treatments for male infertility in the last 10 years? SUMMARY ANSWER Outcome reporting across male infertility trials is heterogeneous with numerous definitions and measures used to define similar outcomes. WHAT IS KNOWN ALREADY No core outcome set for male infertility trials has been developed. Male infertility trials are unique in that they have potentially three participants, a man, a female partner and their offspring and this will likely lead to significant variation in outcome reporting in randomized trials. STUDY DESIGN, SIZE, DURATION A systematic review of RCTs mapping outcomes and outcome measures evaluating potential treatments for men with infertility registered in the Cochrane Register of Controlled Trials (CENTRAL) between January 2010 and July 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS Abstract screening and study selection was undertaken in duplicate using a review protocol that was developed prior to commencing the review. No risk of bias assessment was undertaken as this review aims to report on outcome reporting only. MAIN RESULTS AND THE ROLE OF CHANCE One hundred and seventy-five RCTs were identified, and given the large number of studies we limited our review to the 100 largest trials. Seventy-nine different treatments were reported across the 100 largest RCTs including vitamin and dietary supplements (18 trials), surgical treatments (18 trials) and sperm selection techniques (22 trials). When considering the largest 100 trials (range: 80–2772 participants), 36 primary and 89 secondary outcomes were reported. Forty-seven trials reported a primary outcome and 36 trials clearly defined their primary outcome. Pregnancy outcomes were inconsistently reported and included pregnancy rate (51 trials), pregnancy loss including miscarriage, ectopic pregnancy, stillbirth (9 trials) and live birth (13 trials). Trials consistently reporting the same outcome frequently used different definitions. For example, semen quality was reported by 75 trials and was defined in 7 different ways, including; the World Health Organization (WHO) 2010 criteria (32 trials), WHO 1999 criteria (18 trials), WHO 1992 criteria (3 trials), WHO 1999 and 1992 criteria (1 trial) and the Kruger strict morphology criteria (1 trial). LIMITATIONS, REASONS FOR CAUTION We only evaluated the 100 largest trials published in the last 10 years and did not report outcomes on the remaining 75. An outcome was included as a primary outcome only if clearly stated in the manuscript and we did not contact authors to clarify this. As our review mapped outcomes and outcome measures, we did not undertake an integrity assessment of the trials included in our review. WIDER IMPLICATIONS OF THE FINDINGS Most randomized trials evaluating treatments for male infertility report different outcomes. Only half of the RCTs reported pregnancy rate and even fewer reported live birth; furthermore, the definitions of these outcomes varies across trials. Developing, disseminating and implementing a minimum data set, known as a core outcome set, for male infertility research could help to improve outcome selection, collection and reporting. STUDY FUNDING/COMPETING INTEREST(S) A.P.—chairman of external scientific advisory committee of Cryos International Denmark ApS, member of the scientific advisory board for Cytoswim LDT and ExSeed Health. Guest lecture at the ‘Insights for Fertility Conference’, funded by MERK SERONO Limited. M.v.W.—holds a ZON-MW research grant. No external funding was obtained for this study.

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“…Sikka et al. (2015) concluded that PG did not negatively impact sperm production in healthy volunteers. They reported that a percentage of >50% decrease in sperm count in PG receivers (9.2%) than placebo (3.2%), but the 95% CI was not inferior to placebo statistically and sperm motility decreased by PG administration but did not reach a significant level.…”

Section: Discussionmentioning

confidence: 99%

“…Pregabalin (PG) was associated with reversible effects on sperm parameters (decreased sperm count and motility, and increased sperm abnormalities) and reproductive function (reduced fertility and increased embryo loss) and birth defects in the pre‐clinical animal studies (Ding et al., 2017; Etemad, Mohammad, Mohammadpour, Mashhadi, & Moallem, 2013). However, in clinical trials, treatment with 600 mg/day PG for 12 weeks did not significantly affect spermatogenesis or serum levels of FSH and testosterone in healthy males volunteers (Sikka et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Pregabalin administration and withdrawal affect testicular structure and functions in rats

et al. 2020

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The aim of this prospective experimental study was to investigate the effects of pregabalin (PG) administration and withdrawal on testicular structures and functions in rats. A total of 24 male Wistar rats were divided into two groups (n = 12 each): a control group received normal saline, and PG‐treated group received 62 mg kg‐1 day‐1 PG for 2 months. Half the animals of each group were sacrificed for the collection of blood and testicular samples. The remaining animals were bred for another 2 months without treatment before collection of blood and testicular samples. PG administration decreased testosterone and increased luteinising hormone (LH) and follicle‐stimulating hormone (FSH) levels versus controls. PG withdrawal led to a decrease in both FSH and LH and an increase in testosterone levels versus saline withdrawal. Compared to controls, PG administration caused degeneration of seminiferous tubules and decreased the number of spermatogenic but increased the number of Leydig cells. After PG withdrawal, these cells showed a rebound reverse. Reduced glutathione levels increased with PG administration while PG withdrawal increased malondialdehyde levels. Conclusion: PG administration affected testicular morphometry, gonadotrophic and sex hormones; however, there was a rebound reversal in all these parameters and a significant oxidative stress in PG withdrawal.

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Pregabalin Does Not Affect Sperm Production in Healthy Volunteers: A Randomized, Double‐blind, Placebo‐controlled, Noninferiority Study

Cited by 11 publications

References 12 publications

FDA-approved medications that impair human spermatogenesis

FDA-approved medications that impair human spermatogenesis

Outcome reporting across randomized controlled trials evaluating potential treatments for male infertility: a systematic review

Pregabalin administration and withdrawal affect testicular structure and functions in rats

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