Warfarin Effects on Male Fertility After Cardiac Surgery

Heart Valve Disease, Male Infertility

warfarin, male infertility, Semen quality, Sperm DNA fragmentation, Mitochondrial function, Inflammation, Mechanical heart valve, Cardiac surgery, Oral anticoagulation, Vitamin K antagonists, Reproductive hormones, anticoagulation

Young male patients undergoing cardiac surgery may require oral anticoagulation with warfarin either lifelong, such as after mechanical valve replacement, or for a limited postoperative period, for example following valve repair or bioprosthetic valve implantation. Although the teratogenic effects of warfarin during pregnancy are well established, prospective clinical data on the potential impact of warfarin therapy on male reproductive health are scarce. This gap is particularly relevant for patients of reproductive age who may have a present or future desire for fatherhood. Warfarin acts as a vitamin K antagonist by inhibiting the vitamin K epoxide reductase complex, thereby reducing the availability of functional vitamin K. Beyond its role in coagulation, vitamin K is increasingly recognized as an important regulator of spermatogenesis, mitochondrial function, oxidative balance, and steroid hormone synthesis. Experimental and translational evidence suggests that disruption of vitamin K-dependent pathways may impair sperm quality, DNA integrity, mitochondrial bioenergetics, and reproductive hormone homeostasis. In addition, warfarin exposure has been associated with increased oxidative stress and inflammatory responses, both of which are known contributors to male infertility. Despite these biologically plausible mechanisms, no prospective observational studies have systematically evaluated semen parameters, sperm DNA fragmentation, hormonal profiles, inflammatory markers, and advanced molecular sperm alterations in men exposed to warfarin after cardiac surgery. Consequently, structured andrological assessment is rarely incorporated into routine preoperative counseling or postoperative follow-up in this population. This prospective pilot observational study aims to investigate the association between warfarin therapy and male reproductive health in patients undergoing elective cardiac surgery. Male patients aged 18 to 50 years will be enrolled and observed in three cohorts based on clinical indication for anticoagulation: (1) long-term warfarin therapy following mechanical valve replacement; (2) short-term warfarin therapy (approximately three months) after selected cardiac procedures; and (3) a control cohort undergoing cardiac surgery without an indication for long-term oral anticoagulation beyond standard perioperative prophylaxis. Participants will undergo comprehensive andrological assessments at baseline and during follow-up up to 12 months after surgery. Evaluations will include semen analysis according to World Health Organization guidelines, assessment of sperm DNA fragmentation, reproductive hormonal profiles, and seminal inflammatory markers. Exploratory analyses will assess mitochondrial function, oxidative stress, and molecular alterations in spermatozoa. Detailed warfarin exposure data, including dose, cumulative exposure, international normalized ratio values, and time in therapeutic range, will be collected to explore potential exposure-response relationships. As a pilot study, the primary aims are to assess feasibility and generate preliminary clinical evidence to inform future larger studies. The findings may contribute to improved clinical counseling, fertility preservation strategies, and integration of reproductive health considerations into the multidisciplinary management of young male cardiac surgery patients.

This prospective, comparative, pilot observational study is designed to investigate the effects of warfarin therapy on male reproductive health in patients undergoing elective cardiac surgery, integrating conventional andrological assessment with inflammatory, hormonal, and exploratory molecular analyses. Young male patients undergoing cardiac surgery may require oral anticoagulation with warfarin either lifelong, most commonly after mechanical heart valve replacement, or for a limited postoperative period following selected procedures such as valve repair or bioprosthetic valve implantation. Although the teratogenic effects of warfarin during pregnancy are well established, prospective clinical data addressing its potential impact on male reproductive health are scarce. This knowledge gap is particularly relevant for patients of reproductive age who may have a present or future desire for fatherhood and for whom fertility-related counseling is increasingly important. Warfarin exerts its anticoagulant effect through inhibition of the vitamin K epoxide reductase (VKOR) complex, resulting in reduced availability of biologically active vitamin K. Beyond its role in coagulation, vitamin K-dependent pathways are involved in key aspects of male reproductive physiology, including spermatogenesis, mitochondrial bioenergetics, oxidative stress regulation, inflammatory signaling, and steroid hormone synthesis. Experimental and translational evidence suggests that disruption of these pathways may impair semen quality, sperm DNA integrity, mitochondrial function, and endocrine homeostasis, while promoting oxidative stress and inflammatory responses known to contribute to male infertility. However, these mechanisms have not been systematically explored in prospective clinical studies involving men exposed to warfarin after cardiac surgery. The study adopts a prospective cohort design with a comparative approach and includes three groups of male patients stratified according to clinical indication for anticoagulation: (1) patients receiving long-term warfarin therapy following mechanical valve replacement; (2) patients receiving short-term postoperative warfarin therapy, typically for approximately three months, after selected cardiac surgical procedures; and (3) a control group undergoing cardiac surgery without indication for long-term oral anticoagulation beyond standard perioperative prophylaxis. This design allows evaluation of different exposure patterns, including chronic exposure, transient exposure, and non-exposure, and supports exploratory assessment of exposure-response relationships and reversibility after treatment discontinuation. Participants undergo structured and standardized andrological evaluations at baseline (preoperative) and during longitudinal follow-up up to 12 months after surgery. Conventional semen analysis is performed according to World Health Organization (WHO) guidelines and includes assessment of sperm concentration, progressive motility, morphology, and related semen parameters. Sperm DNA integrity is evaluated through measurement of the sperm DNA fragmentation index (DFI) using the sperm chromatin dispersion (SCD) assay. Reproductive endocrine function is assessed through serial measurement of serum reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, sex hormone-binding globulin (SHBG), prolactin, and thyroid-stimulating hormone (TSH), using standardized laboratory immunoassay methods. Local inflammatory processes within the male reproductive tract are investigated through assessment of seminal inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α). These biomarkers are measured using standardized enzyme-linked immunosorbent assay (ELISA) techniques and evaluated in relation to semen quality parameters. To provide mechanistic insight beyond conventional clinical and laboratory assessments, exploratory molecular analyses are performed on spermatozoa. These analyses include evaluation of mitochondrial function and bioenergetics, assessment of oxidative stress-related parameters, and analysis of selected proteins involved in sperm energy metabolism and motility, using validated laboratory techniques. These exploratory investigations are intended to characterize molecular alterations potentially associated with warfarin exposure and to generate hypotheses for future mechanistic studies. Detailed warfarin exposure data are collected prospectively from clinical records and anticoagulation monitoring systems, including daily and cumulative dosing information, international normalized ratio (INR) measurements, and quality of anticoagulation control over time as reflected by time in therapeutic range (TTR). These exposure variables are used to support exploratory correlation analyses with reproductive, inflammatory, and molecular outcomes, as well as evaluation of potential reversibility of observed alterations in patients receiving short-term warfarin therapy after treatment discontinuation. Sexual and reproductive function is further characterized through validated questionnaires assessing sexual function, including the International Index of Erectile Function-5 (IIEF-5), and through collection of exploratory reproductive outcomes, such as desire for paternity and occurrence of partner pregnancies during follow-up. As a pilot study, the primary objectives are to assess feasibility, characterize longitudinal changes in male reproductive parameters, and generate preliminary clinical and mechanistic data to inform the design of future larger-scale studies. The findings are expected to contribute to improved fertility-related counseling, consideration of fertility preservation strategies, and integration of reproductive health assessment into the multidisciplinary management of young male patients undergoing cardiac surgery.

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