What is Sertoli‑cell‑only syndrome and how is it treated in a male with non‑obstructive azoospermia?

Sertoli Cell-Only Syndrome: Definition and Treatment

What is Sertoli Cell-Only Syndrome?

Sertoli cell-only syndrome (SCOS), also known as germ cell aplasia, is the most severe histological form of non-obstructive azoospermia, characterized by complete absence of germ cells in the seminiferous tubules with only Sertoli cells remaining. 1, 2

Clinical Characteristics

• SCOS presents with azoospermia (complete absence of sperm in the ejaculate) and is definitively diagnosed only by testicular biopsy showing seminiferous tubules lined exclusively with Sertoli cells 2, 3

• Men with SCOS typically present with low testicular volume, normal semen volume, and elevated FSH levels (usually >7.6 IU/L) 1

• The Sertoli cells themselves appear morphologically normal under microscopy, though they adopt a columnar shape due to the absence of germ cells 4

Genetic Associations

• Complete deletion of the AZFa region of the Y chromosome is specifically associated with SCOS, and these deletions predict near-zero likelihood of sperm retrieval 1

• TESE should not be attempted in patients with complete AZFa or AZFb deletions, as the prognosis for surgical sperm retrieval is almost zero 1

• While SCOS can result from Klinefelter syndrome, most men with SCOS have a normal karyotype, making genetic testing essential for all azoospermic patients 1, 2

Treatment Approach for SCOS

Mandatory Genetic Testing Before Treatment

• Karyotype analysis and Y-chromosome microdeletion testing (AZFa, AZFb, AZFc regions) are mandatory for all men with azoospermia before considering any sperm retrieval procedures 1

• This testing is critical because complete AZFa and AZFb deletions contraindicate TESE procedures entirely 1

Surgical Sperm Retrieval: The Only Effective Treatment

Microdissection testicular sperm extraction (micro-TESE) is the gold standard treatment for SCOS, as it offers the best chance of finding focal areas of sperm production, though success rates remain limited. 1, 5

Micro-TESE Technique and Outcomes

• Micro-TESE uses operative microscopy to identify seminiferous tubules more likely to harbor sperm, increasing retrieval probability while minimizing tissue damage 1

• In men with non-obstructive azoospermia including SCOS, micro-TESE achieves sperm retrieval in approximately 40-50% of cases, which is 1.5 times more successful than conventional TESE 1, 5

• The rationale for micro-TESE is that SCOS may not be uniformly distributed throughout the testis—focal areas of spermatogenesis may still exist in some tubules 1, 6

• Lower complication rates (hematoma and fibrosis) occur with micro-TESE compared to conventional TESE 1

Important Caveats About Sperm Retrieval

• The presence of hypospermatogenesis at testicular biopsy predicts better sperm retrieval outcomes than maturation arrest or SCOS patterns 1

• Hormonal levels including FSH, LH, inhibin B, and AMH show variable correlation with sperm retrieval outcomes, with data limited to retrospective series 1

• Testicular volume as a predictor of positive sperm retrieval has been inconsistent in SCOS 1

What NOT to Do: Contraindicated Treatments

• Never prescribe exogenous testosterone to men with SCOS who desire fertility, as it completely suppresses the hypothalamic-pituitary-gonadal axis, causing complete cessation of spermatogenesis 5

• Empirical medical treatments (FSH analogues, SERMs, aromatase inhibitors) have extremely limited efficacy in SCOS and should not delay more effective assisted reproductive technology options 5

• Fine needle aspiration (FNA) mapping is not recommended as a primary diagnostic procedure before TESE, as it requires two surgical procedures when one may be sufficient and lacks supporting RCT evidence 1

Assisted Reproductive Technology After Sperm Retrieval

• If sperm are successfully retrieved via micro-TESE, intracytoplasmic sperm injection (ICSI) with in vitro fertilization (IVF) provides the most reliable path to achieving pregnancy 5, 2

• For couples where micro-TESE fails to retrieve sperm, the only options are donor sperm or adoption 5

Emerging Understanding of SCOS Pathophysiology

• Recent evidence suggests that in some cases (when genetic problems are excluded), SCOS may represent the final stage of longstanding testicular hypoxia rather than an independent disease entity 6

• In select cases without genetic abnormalities, adequate correction of bilateral varicocele by microsurgery restored limited sperm production in 4 out of 10 patients with SCOS, though this remains investigational 6

Critical Counseling Points

• Patients must understand that even with micro-TESE, only 40-50% will have retrievable sperm, meaning half will have no biological fertility options 1, 5

• Testosterone deficiency may worsen after micro-TESE, potentially requiring subsequent testosterone replacement once fertility goals are abandoned 5

• Genetic counseling is essential, as any retrieved sperm may carry genetic abnormalities (particularly Y-chromosome microdeletions) that will be transmitted to male offspring 1