Probenecid for Male Infertility Due to Spinal Cord Injury

Overseen By Odaro Ugbo, BSc

Age: 18+

Sex: Male

Trial Phase: Phase 3

Sponsor: University of Miami

Must not be taking: Methotrexate, Aspirin, Salicylates, Anti-inflammatories

Disqualifiers: Azoospermia, Foley catheter, Unstable condition, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a study of infertility which often occurs in men with spinal cord injury. Most men with spinal cord injury have a normal sperm count but abnormally low sperm motility - which means that the sperm does not swim well. This study will determine if a medicine given by mouth will improve sperm motility in men with spinal cord injuries. The medicine is called probenecid.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking methotrexate, aspirin, other salicylates, or anti-inflammatory medicines to participate in the trial.

Is Probenecid safe for human use?

Probenecid has been used safely in humans for other conditions, but specific safety data for its use in treating male infertility due to spinal cord injury is not available. Generally, it is important to consult with a healthcare provider to understand potential risks and benefits. ^{1 2 3 4 5}

How does the drug Probenecid differ from other treatments for male infertility due to spinal cord injury?

Probenecid is unique because it is primarily used to treat gout by increasing uric acid excretion, and its use for male infertility due to spinal cord injury is novel, as traditional treatments focus on managing erectile and ejaculatory dysfunctions or improving semen quality through methods like vibratory stimulation or electroejaculation. ^{6 7 8 9 10}

Research Team

Emad Ibrahim, MD

Principal Investigator

University of Miami

Eligibility Criteria

This trial is for men over 18 with traumatic spinal cord injury who have been injured for at least a year. It's not for those with zero sperm count, indwelling catheters, unstable conditions like Crohn's or colon cancer, implanted electrical devices, allergies to probenecid, history of kidney stones/ulcers, recent UTI fever, or taking certain medications.

Inclusion Criteria

I am a man aged 18 or older.

I have a spinal cord injury due to trauma.

Exclusion Criteria

I cannot safely undergo the procedure or take the medication.

Subject has been injured less than 1 year

Subject is known to be azoospermic

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a placebo, full dose, or half dose of probenecid for a total of 90 days

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Treatment Details

Interventions

• Probenecid

Trial Overview The study tests if probenecid can improve the swimming ability of sperm in men with spinal cord injuries. Participants will receive either a placebo (no active ingredient) or probenecid at doses of 250 mg or 500 mg to see which works better.

Participant Groups

Group I: Half dose group Experimental Treatment 1 Intervention

Participants in this group will receive half the dose of probenecid for a total of 90 days.

Group II: Full dose group Experimental Treatment 1 Intervention

Participants in this group will receive the full dose of probenecid for a total of 90 days.

Group III: Control-placebo group Placebo Group 1 Intervention

Participants in this group will receive a placebo dose (No active ingredient) for a total of 90 days.

Probenecid is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Benemid for:

• Gout
• Hyperuricemia

Approved in Canada as Probecid for:

• Gout
• Hyperuricemia

Approved in European Union as Probenecid for:

• Gout
• Hyperuricemia

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

Benomyl, a widely used fungicide, primarily affects the male reproductive system by disrupting microtubules in Sertoli cells, leading to sloughing of germ cells and abnormal development of sperm, particularly at moderate to low doses.

At higher doses, benomyl causes occlusion of the efferent ducts, which blocks sperm passage and can lead to testicular swelling, tubular atrophy, and infertility, highlighting the need for careful evaluation of long-term testicular health in studies involving toxicants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histopathology of the male reproductive system induced by the fungicide benomyl. Hess, RA., Nakai, M.[2018]

Certain cardiovascular and respiratory medications, particularly some α1-adrenergic antagonists and atenolol, have been linked to sexual dysfunction and may impact male reproductive health, including risks of retrograde ejaculation and decreased testosterone levels.

Despite concerns, many commonly used medications like calcium channel blockers show significant effects on sperm function in laboratory settings, but lack strong evidence of negatively affecting semen quality or fertility in real-life scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular/Pulmonary Medications and Male Reproduction. Drobnis, EZ., Nangia, AK.[2018]

Male infertility is increasingly common, particularly among men, with many cases having unknown causes; however, the impact of drugs on male fertility has been under-researched, especially in humans.

The article highlights various drugs known to negatively affect male fertility, emphasizing the need for more research, including clinical trials and post-marketing surveillance, to better understand these risks and their mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions on male fertility. Lacroix, I.[2023]

A study of 34 men exposed to methylene chloride revealed that 8 of them experienced reproductive issues, including testicular and lower abdominal pain, which were linked to prostatic problems.

Semen analysis from four volunteers indicated subfertility, showing reduced sperm motility, morphology, and density, suggesting that methylene chloride exposure may negatively impact male reproductive health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case reports of individuals with oligospermia and methylene chloride exposures. Kelly, M.[2019]

In a 70-day study with male Wistar rats, high doses of the fungicide benomyl (203 ppm) significantly reduced sperm counts and testicular weights, indicating potential reproductive harm.

However, these negative effects were reversible, as a subsequent 70-day recovery period showed that sperm counts, testicular weights, and fertility indices returned to normal levels, suggesting that the damage caused by benomyl is not permanent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reproductive toxicity of methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) in male Wistar rats. Barnes, TB., Verlangieri, AJ., Wilson, MC.[2019]

Men with spinal cord injuries often face infertility due to poor semen quality and ejaculatory dysfunction, with only 5% of those with complete upper motor lesions able to ejaculate, compared to up to 70% of men with incomplete lesions.

Effective methods for inducing ejaculation, such as electroejaculation (85% success) and vibratory stimulation (59% success), are available, but require careful monitoring due to risks like autonomic dysreflexia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infertility in men with spinal cord injury. Linsenmeyer, TA., Perkash, I.[2005]

Men with spinal cord injury (SCI) often face infertility due to erectile dysfunction, ejaculatory dysfunction, and abnormal semen quality, but various management options like PDE-5 inhibitors and assisted ejaculation methods (PVS and EEJ) can help address these issues.

Despite having sufficient motile sperm for less invasive procedures like intrauterine insemination (IUI), many couples are prematurely directed towards more invasive and costly methods like IVF/ICSI, highlighting the need for better education on all available fertility options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Male fertility following spinal cord injury: an update. Ibrahim, E., Lynne, CM., Brackett, NL.[2016]

In a review of 113 males with spinal cord injuries, electroejaculation was highly effective for semen retrieval (97%), while vibroejaculation was also successful (67%), demonstrating the efficacy of these methods in managing male infertility.

The overall pregnancy rate per cycle for couples seeking assistance was 18%, with a cumulative pregnancy rate of 55%, indicating that specialized fertility treatments can lead to successful outcomes, including 14 live births from 17 pregnancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive approach to the management of male infertility following spinal cord injury. Rutkowski, SB., Geraghty, TJ., Hagen, DL., et al.[2019]

Spinal cord injury (SCI) patients often experience various sexual disorders, including erectile dysfunction, and a structured treatment approach is recommended, starting with lifestyle changes and progressing to medications and surgical options.

For male SCI patients, treatments for erectile dysfunction and anejaculatory dysfunction can involve a combination of methods, including PDE5 inhibitors, penile prostheses, and assisted reproductive techniques, while female patients have similar management strategies without the need for erectile treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of sexual disorders in spinal cord injured patients. Rahimi-Movaghar, V., Vaccaro, AR.[2018]

Most men with spinal cord injury (SCI) experience infertility due to erectile dysfunction and semen abnormalities, but sperm from these men can still lead to successful pregnancies, indicating potential for reproductive success despite challenges.

Penile vibratory stimulation is the first-line treatment for achieving ejaculation in anejaculatory patients, and if unsuccessful, other methods like electroejaculation or surgical sperm retrieval can be considered, with reproductive outcomes comparable to those of men without SCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of infertility in men with spinal cord injury. Brackett, NL., Lynne, CM., Ibrahim, E., et al.[2021]

References

1. Spain pubmed.ncbi.nlm.nih.gov

Histopathology of the male reproductive system induced by the fungicide benomyl. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular/Pulmonary Medications and Male Reproduction. [2018]

3. France pubmed.ncbi.nlm.nih.gov

Adverse drug reactions on male fertility. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Case reports of individuals with oligospermia and methylene chloride exposures. [2019]

5. Ireland pubmed.ncbi.nlm.nih.gov

Reproductive toxicity of methyl-1-(butylcarbamoyl)-2-benzimidazole carbamate (benomyl) in male Wistar rats. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Infertility in men with spinal cord injury. [2005]

7. England pubmed.ncbi.nlm.nih.gov

Male fertility following spinal cord injury: an update. [2016]

8. England pubmed.ncbi.nlm.nih.gov

A comprehensive approach to the management of male infertility following spinal cord injury. [2019]

9. Iran pubmed.ncbi.nlm.nih.gov

Management of sexual disorders in spinal cord injured patients. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Treatment of infertility in men with spinal cord injury. [2021]