Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men

NCT07402759 | Active Not Recruiting Phase 3

• 1 other identifier: Svu-med-dva021-4-25-12-5
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Infertility remains a significant global burden. Estimates suggest that 10-15% of couples worldwide experience infertility, with male infertility being the underlying cause in 20-50% of cases. For the majority of cases however the etiology remains unknown, and is termed idiopathic infertility. Azoospermia, absence of spermatozoa in the semen, is one of the most common reasons for infertility in men, with a prevalence of 1% in the general population, and over 15% in infertile men. Oligozoospermia is a major cause of male infertility, yet its genetic basis remains partially understood. Oligozoospermia refers to sperm concentrations below established reference limits (e.g. 16 million/ml, 95% confidence interval 15-18 million/ml; WHO 2021). Numerous studies have demonstrated a strong genetic basis for oligozoospermia, with genetic abnormalities, such as abnormalities in chromosome number or structure, azoospermia factor region (AZF) deletion on the Y chromosome and cystic fbrosis transmembrane conduction regulator (CFTR) gene mutations, reported in men with otherwise unexplained oligozoospermia and azoospermia. Moreover, previous studies have identifed more than 400 genes that are specifcally or potentially associated with fertility regulation while potentially contributing to the widespread genetic heterogeneity associated with dyszoospermia. For example, mutations in RPL10L and MAGEB have been reported to cause oligozoospermia. However, mutations in only a few genes have been shown to cause male infertility, and the candidate pathogenic genes for oligozoospermia still need to be studied further. Recent studies have implicated the Tudor Domain Containing 9 (TDRD9) gene in the regulation of spermatogenesis through its role in piRNA pathway and transposon silencing. A 2024 study identified compound heterozygous mutations-c.1115+3A\>G (splicing variant) and c.958delC (frameshift variant)-in a Chinese family with idiopathic oligozoospermia, resulting in aberrant splicing and truncated TDRD9 protein products. Tudor domain-containing protein 9 (TDRD9) is an RNA helicase that is highly expressed in germlines. TDRD9 expression has been detected in mitotic spermatogonia, meiotic spermatocytes and haploid spermatids in the testis. In male infertility cases, TDRD9 has been reported to be involved in the silencing of long intersperm-1 retrotransposons, suggesting an association between TDRD9 mutations and non-obstructive azoospermia. TDRD9 is implicated in spermatogenesis and piRNA pathway integrity. Variants may affect sperm quality and response to treatments. L-carnitine is widely used as an antioxidant and metabolic supplement shown to improve sperm parameters in some infertile men. This study will test whether TDRD9 mutation status predicts therapeutic benefit from L-carnitine.

Conditions

Oligoasthenozoospermia; Male Infertility

Keywords

Tdrd9; L-carnitine; Sperm motility; Semen analysis; Total motile sperm count

Outcome Measures

Primary Outcomes (1)

• Change in total motile sperm count (TMSC) from baseline to 3 months

  Total motile sperm count (TMSC), calculated as semen volume × sperm concentration × percentage of progressively motile sperm, measured at baseline and after 3 months of oral L-carnitine therapy. The outcome is expressed as the mean change in TMSC (million motile sperm per ejaculate) from baseline to 3 months and compared between men with and without TDRD9 gene mutations. Unit of Measure: Million motile sperm per ejaculate

  Baseline to 3 months

Secondary Outcomes (4)

• Change in sperm concentration from baseline to 3 months

  Baseline to 3 months

• Change in normal sperm morphology from baseline to 3 months

  Baseline to 3 months

• Change in semen volume from baseline to 3 months

  Baseline to 3 months

• Change in serum follicle-stimulating hormone (FSH) levels from baseline to 3 months

  Baseline to 3 months

Study Arms (1)

Tdrd9 positive and negative

EXPERIMENTAL

L-carnitine

Drug: L-carnitine

Interventions

L-carnitine DRUG

Dietary supplement

Tdrd9 positive and negative

Eligibility Criteria

• Age: 20 Years - 50 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Clinical diagnosis of oligoasthenozoospermia, confirmed by two semen analyses according to WHO 2010/2021 criteria:

Sponsors & Collaborators

• South Valley University: lead

Study Sites (1)

Qena university hospital

Cairo, Egypt

Location

Related Publications (5)

• Lahimer M, Gherissi O, Ben Salem N, Ben Mustapha H, Bach V, Khorsi-Cauet H, Khairi H, Ben Ali H, BenKhalifa M, Ajina M. Effect of micronutrients and L-carnitine as antioxidant on sperm parameters, genome integrity, and ICSI outcomes: randomized, double-blind, and placebo-controlled clinical trial. Antioxidants. 2023 Oct 31;12(11):1937.

  BACKGROUND

• Okutman O, et al. A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family. J Assist Reprod Genet. 2017;34(5):683-94.

  BACKGROUND

• Esteves SC. Who cares about oligozoospermia when we have ICSI. Reproductive biomedicine online. 2022 May 1;44(5):769-75.

  BACKGROUND

• Wang W, Feng Y, Dong J, Zhou Z, Jing J, Li Z, Chen L, Lin X, Ma J, Yao B. A Novel Compound Heterozygous Mutation in TDRD9 Causes Oligozoospermia. Reproductive Sciences. 2024 Nov;31(11):3413-9.

  BACKGROUND

• Babakhanzadeh E, Khodadadian A, Rostami S, Alipourfard I, Aghaei M, Nazari M, Hosseinnia M, Mehrjardi MY, Jamshidi Y, Ghasemi N. Testicular expression of TDRD1, TDRD5, TDRD9 and TDRD12 in azoospermia. BMC medical genetics. 2020 Dec; 21:1-7. rmia when we have ICSI. Reproductive biomedicine online. 2022 May 1;44(5):769-75.

  BACKGROUND

MeSH Terms

Conditions

Infertility, Male

Interventions

Carnitine

Condition Hierarchy (Ancestors)

Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals

Study Officials

• Eisa Mohammed Hegazy

  South Valley University

  STUDY DIRECTOR

• Mahmoud Ahmed Ali, Assistant professor

  Aswan University Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Resident at dermatology, venereology and andrology department south valley university hospital, principal investigator

Study Record Dates

• First Submitted: January 18, 2026
• First Posted: February 11, 2026
• Study Start: January 1, 2026
• Primary Completion: June 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: February 11, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

EG (1)