Warfarin Effects on Male Fertility After Cardiac Surgery

NCT07330869 | Not Yet Recruiting

• 1 other identifier: WARF-SEMIN-2025-01
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Male Infertility; Heart Valve Disease

Keywords

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

Outcome Measures

Primary Outcomes (3)

• Change in sperm concentration over time

  Change in sperm concentration expressed as millions of spermatozoa per milliliter (millions/mL), assessed by standard semen analysis performed according to World Health Organization (WHO) guidelines. Correlation between warfarin exposure status (long-term exposure, short-term exposure, or no exposure) and changes in sperm concentration over time will be evaluated.

  Baseline (T0) to 6 months (T2) and 12 months (T3)

• Change in progressive sperm motility over time

  Change in progressive sperm motility expressed as percentage (%), assessed by standard semen analysis according to World Health Organization (WHO) guidelines. Correlation between warfarin exposure status (long-term exposure, short-term exposure, or no exposure) and changes in progressive sperm motility over time will be evaluated.

  Baseline (T0) to 6 months (T2) and 12 months (T3)

• Change in sperm morphology over time

  Change in the percentage (%) of spermatozoa with normal morphology, assessed using strict criteria as part of standard semen analysis according to World Health Organization (WHO) guidelines. Correlation between warfarin exposure status (long-term exposure, short-term exposure, or no exposure) and changes in sperm morphology over time will be evaluated.

  Baseline (T0) to 6 months (T2) and 12 months (T3)

Secondary Outcomes (23)

• Change in sperm DNA fragmentation index (DFI)

  Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)

• Change in serum follicle-stimulating hormone (FSH) levels

  Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)

• Change in serum luteinizing hormone (LH) levels

  Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)

• Change in serum total testosterone levels

  Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)

• Change in serum sex hormone-binding globulin (SHBG) levels

  Baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3)

Study Arms (3)

Long-term Warfarin Group

Male patients undergoing cardiac surgery with an indication for lifelong oral anticoagulation with warfarin, typically after mechanical heart valve replacement. Warfarin therapy is prescribed as part of standard clinical care and is not assigned by the study.

Other: Semen analysis, sperm DNA fragmentation and hormonal evaluation

Short-term Warfarin Group

Male patients undergoing cardiac surgery with an indication for short-term postoperative warfarin therapy (approximately three months), such as after valve repair or bioprosthetic valve implantation. Anticoagulation is administered according to standard clinical practice and not determined by the study protocol.

Other: Semen analysis, sperm DNA fragmentation and hormonal evaluation

Control Group (No Long-term Anticoagulation)

Male patients undergoing cardiac surgery without an indication for long-term oral anticoagulation beyond routine perioperative prophylaxis. These patients serve as a comparison group and do not receive chronic warfarin therapy.

Other: Semen analysis, sperm DNA fragmentation and hormonal evaluation

Interventions

Semen analysis, sperm DNA fragmentation and hormonal evaluation OTHER

Participants undergo standardized study assessments including semen analysis according to WHO criteria, sperm DNA fragmentation assessment, hormonal blood tests, andrological ultrasound, and exploratory molecular analyses of spermatozoa (mitochondrial function, oxidative stress markers, inflammatory mediators, and protein expression). All assessments are performed for observational and research purposes only and do not guide or modify clinical treatment.

Control Group (No Long-term Anticoagulation); Long-term Warfarin Group; Short-term Warfarin Group

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

This study will enroll male patients aged 18 to 50 years undergoing elective cardiac surgery at a high-volume cardiac surgery center. Participants will include individuals requiring either lifelong Warfarin therapy (mechanical heart valve replacement), short-term postoperative Warfarin therapy (e.g., mitral valve repair or bioprosthetic valve implantation), or no long-term anticoagulation beyond routine perioperative prophylaxis. Eligible patients must have no previous diagnosis of male infertility, must be able and willing to provide semen samples at scheduled follow-up timepoints, and must provide written informed consent. Patients with severe testicular disease, prior chemotherapy or radiotherapy, endocrine disorders affecting spermatogenesis, active genitourinary infection, or current/recent use of anabolic steroids or medications known to impair spermatogenesis will be excluded.

You may qualify if:

• Male sex, age between 18 and 50 years;
• Scheduled for elective cardiac surgery (valve replacement, valve repair, or other cardiac procedures) with or without indication to Warfarin therapy;
• Ability and willingness to provide semen samples at scheduled timepoints;
• No previous diagnosis of male infertility documented in medical records;
• Signed informed consent.

You may not qualify if:

• Known severe testicular pathology (for example, untreated high-grade varicocele, history of cryptorchidism, orchiectomy, testicular tumors);
• Prior chemotherapy or pelvic radiotherapy;
• Current or recent use of anabolic steroids or other drugs known to strongly impair spermatogenesis;
• Known endocrine disorders affecting spermatogenesis (for example, untreated hypogonadism, hyperprolactinaemia, severe thyroid disease);
• Active genitourinary infection at the time of evaluation;
• Life expectancy less than 12 months or clinical conditions preventing adherence to follow-up.

Sponsors & Collaborators

• Città di Lecce Hospital, GVM Care & Research: lead

Study Sites (1)

Città di Lecce Hospital - Department of Cardiac Surgery

Lecce, LE, 73100, Italy

Location

Related Publications (10)

• Popov A, Belij S, Subota V, Zolotarevski L, Mirkov I, Kataranovski D, Kataranovski M. Oral warfarin affects peripheral blood leukocyte IL-6 and TNFalpha production in rats. J Immunotoxicol. 2013 Jan-Mar;10(1):17-24. doi: 10.3109/1547691X.2012.684159. Epub 2012 Jul 13.

  PMID: 22793260 RESULT

• Azenabor A, Ekun AO, Akinloye O. Impact of Inflammation on Male Reproductive Tract. J Reprod Infertil. 2015 Jul-Sep;16(3):123-9.

  PMID: 26913230 RESULT

• Ma H, Zhang BL, Liu BY, Shi S, Gao DY, Zhang TC, Shi HJ, Li Z, Shum WW. Vitamin K2-Dependent GGCX and MGP Are Required for Homeostatic Calcium Regulation of Sperm Maturation. iScience. 2019 Apr 26;14:210-225. doi: 10.1016/j.isci.2019.03.030. Epub 2019 Mar 29.

  PMID: 30981116 RESULT

• Shiba S, Ikeda K, Horie-Inoue K, Azuma K, Hasegawa T, Amizuka N, Tanaka T, Takeiwa T, Shibata Y, Koji T, Inoue S. Vitamin K-Dependent gamma-Glutamyl Carboxylase in Sertoli Cells Is Essential for Male Fertility in Mice. Mol Cell Biol. 2021 Mar 24;41(4):e00404-20. doi: 10.1128/MCB.00404-20. Print 2021 Mar 24.

  PMID: 33526452 RESULT

• Alfano M, Pederzoli F, Locatelli I, Ippolito S, Longhi E, Zerbi P, Ferrari M, Brendolan A, Montorsi F, Drago D, Andolfo A, Nebuloni M, Salonia A. Impaired testicular signaling of vitamin A and vitamin K contributes to the aberrant composition of the extracellular matrix in idiopathic germ cell aplasia. Fertil Steril. 2019 Apr;111(4):687-698. doi: 10.1016/j.fertnstert.2018.12.002.

  PMID: 30929729 RESULT

• Shirakawa H, Ohsaki Y, Minegishi Y, Takumi N, Ohinata K, Furukawa Y, Mizutani T, Komai M. Vitamin K deficiency reduces testosterone production in the testis through down-regulation of the Cyp11a a cholesterol side chain cleavage enzyme in rats. Biochim Biophys Acta. 2006 Oct;1760(10):1482-8. doi: 10.1016/j.bbagen.2006.05.008. Epub 2006 Jun 6.

  PMID: 16844298 RESULT

• Sanyaolu AO, Oremosu AA, Osinubi AA, Vermeer C, Daramola AO. Warfarin-induced vitamin K deficiency affects spermatogenesis in Sprague-Dawley rats. Andrologia. 2019 Nov;51(10):e13416. doi: 10.1111/and.13416. Epub 2019 Oct 1.

  PMID: 31576592 RESULT

• Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, Blomstrom-Lundqvist C, Cifkova R, De Bonis M, Iung B, Johnson MR, Kintscher U, Kranke P, Lang IM, Morais J, Pieper PG, Presbitero P, Price S, Rosano GMC, Seeland U, Simoncini T, Swan L, Warnes CA; ESC Scientific Document Group. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018 Sep 7;39(34):3165-3241. doi: 10.1093/eurheartj/ehy340. No abstract available.

  PMID: 30165544 RESULT

• Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000 Jan 24;160(2):191-6. doi: 10.1001/archinte.160.2.191.

  PMID: 10647757 RESULT

• Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980 Jan;68(1):122-40. doi: 10.1016/0002-9343(80)90181-3.

  PMID: 6985765 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Semen samples and blood samples will be collected and retained for planned analyses, including standard semen parameters, sperm DNA fragmentation assessment, hormonal assays and exploratory molecular analyses related to mitochondrial function, oxidative stress, inflammatory markers, and protein expression.

MeSH Terms

Conditions

Infertility, Male; Heart Valve Diseases; Inflammation

Interventions

Semen Analysis

Condition Hierarchy (Ancestors)

Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Central Study Contacts

Giuseppe Santarpino, MD, PhD

CONTACT

+393246940566; gsantarpino@gvmnet.it

Veronica D'Anna, MSc

CONTACT

+39 3891437634; veronicadanna21@gmail.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2025
• First Posted: January 9, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): June 1, 2028
• Last Updated: January 9, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)