Exosome Therapy Prior to Repeat Microdissection TESE in a Patient with Non-Obstructive Azoospermia: A Case Report
Onur Dede1*; Mazhar Utanğac1; Ece Yilmaz Eşsiz2
¹Department Of Urology, Dicle University, Diyarbakir, Turkey
²Department Of Pathology, Dicle University, Diyarbakir, Turkey
*Corresponding author
Onur Dede , Department Of Urology, Dicle University, Diyarbakir, Turkey
E-mail: dronurdede@hotmail.com
DOI: 10.55920/JCRMHS.2025.13.001572
Abstract
Background: Non-obstructive azoospermia (NOA) is a major cause of male infertility, often characterized by severely impaired spermatogenesis and unfavorable testicular histology. The chance of sperm retrieval in patients with Sertoli cell-only (SCO) pattern is particularly poor. Novel cell-free therapies, such as exosome-based approaches, have been suggested to modulate the testicular microenvironment.
Case Presentation: We present a 27-year-old male with elevated gonadotropins (FSH 17 IU/L, LH 9 IU/L), low total testosterone (2.4 ng/mL), and bilaterally atrophic testes. Initial microdissection testicular sperm extraction (mTESE) revealed SCO in both testes with no sperm retrieved. Following a single intratesticular exosome injection into the right testis, repeat mTESE three months later demonstrated persistent SCO in the left testis but hypospermatogenesis in the right testis. Importantly, spermatozoa were successfully retrieved from the right testis and cryopreserved.
Conclusion: This case highlights the potential role of exosome therapy as an adjunctive approach to improve spermatogenesis and enable sperm retrieval in NOA patients with prior SCO histology.
Keywords: Non-Obstructive Azoospermia, Sertoli Cell-Only, Exosome Therapy, Microdissection Tese, Male Infertility
Introduction
Non-obstructive azoospermia (NOA) accounts for approximately 10–15% of all infertile men and represents the most severe form of spermatogenic failure [1]. Microdissection testicular sperm extraction (mTESE) is currently the most effective surgical technique for sperm retrieval in NOA patients [2]. However, retrieval rates remain low in those with Sertoli cell-only (SCO) histology [3].
Emerging regenerative strategies have focused on the use of stem cells, growth factors, and extracellular vesicles. Among these, exosomes—nano-sized extracellular vesicles secreted by various cells—play an important role in intercellular communication and tissue regeneration [4]. Preclinical evidence suggests that exosomes derived from Sertoli cells, mesenchymal stem cells (MSCs), or germ cells may support spermatogenesis by modulating oxidative stress, apoptosis, and stem cell niches [5–8].
Here, we present the first human case in which exosome therapy was associated with histological improvement from SCO to hypospermatogenesis and successful sperm retrieval on repeat mTESE.
Case Presentation
A 27-year-old male presented with a history of primary infertility. He had no significant comorbidities, history of undescended testis, orchitis, or gonadotoxic therapy.
Physical examination: Bilateral atrophic, soft testes without varicocele.
Hormonal evaluation:
- FSH: 17 IU/L (elevated)
- LH: 9 IU/L (elevated)
- Total testosterone: 2.4 ng/mL (low)
Scrotal ultrasound confirmed reduced testicular volume bilaterally. Karyotyping revealed 46,XY, and Y chromosome microdeletion testing was negative.
An initial mTESE was performed, revealing Sertoli cell-only (SCO) syndrome bilaterally, with no sperm retrieved.
As an experimental approach, the patient underwent a single intratesticular injection of purified exosomes into the right testis under ultrasound guidance.
Three months later, a repeat mTESE was performed. Histopathological evaluation showed (FIGURE 1)
- Left testis: persistent SC
- Right testis: hypospermatogenesis
Spermatozoa were successfully retrieved from the right testis and cryopreserved for use in ICSI. The patient is currently undergoing follow-up in preparation for ART.
Figure 1: Left testis: persistent SC X20 Right testis: hypospermatogenesis X20
Discussion
The present case demonstrates a potential association between intratesticular exosome therapy and recovery of spermatogenic activity in a patient with non-obstructive azoospermia and initial SCO histology. Traditionally, SCO is considered one of the poorest prognostic patterns for sperm retrieval, with reported success rates below 20% [3]. In our patient, while the first mTESE yielded no sperm, the second procedure after exosome therapy revealed focal hypospermatogenesis and allowed successful retrieval.
Exosomes are known to carry bioactive molecules such as proteins, mRNAs, and microRNAs, which can regulate gene expression and intercellular signaling [4]. Their role in reproductive biology has been increasingly recognized, as they facilitate communication between Sertoli cells, germ cells, and the testicular niche.
Several experimental studies have shown that exosomes may support or restore spermatogenesis. Mao et al. demonstrated that exosomes derived from Sertoli cells improved spermatogenic recovery in murine models of azoospermia [5]. Similarly, Guo et al. reported that mesenchymal stem cell-derived exosomes ameliorated busulfan-induced testicular injury and promoted spermatogenesis in mice [6]. Ding et al. confirmed these findings in rat models, showing that adipose-derived MSC exosomes enhanced spermatogenesis and testosterone production after gonadotoxic damage [7]. Furthermore, Qamar et al. reviewed preclinical data and emphasized that exosomes alleviate oxidative stress and apoptosis in germ cells, thereby preserving spermatogenic potential [8].
Our findings align with this body of evidence, as the patient’s right testis demonstrated histological improvement from SCO to hypospermatogenesis after exosome therapy. While causality cannot be definitively established from a single case, the temporal relationship and concordance with preclinical studies suggest that exosome treatment may have contributed to the observed outcome.
This case is, to our knowledge, the first human report linking exosome therapy with improved spermatogenesis and sperm retrieval in NOA. If validated in larger clinical studies, exosome-based interventions could provide a minimally invasive, cell-free alternative to stem cell transplantation for selected NOA patients.
The primary limitation of this report is its single-patient nature. The observed improvement may represent focal heterogeneity in testicular histology rather than a direct therapeutic effect. Longitudinal, controlled clinical trials are required to confirm efficacy and safety before routine clinical use can be recommended.
Conclusion
Exosome therapy may serve as a novel adjunct to conventional surgical sperm retrieval in NOA patients with unfavorable testicular histology. Our case demonstrates, for the first time in humans, an association between exosome injection and histological improvement enabling sperm retrieval. This strategy warrants further clinical investigation.
References
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