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Late Effects



Testicular Damage


Testicular function:

  • Sperm production
    • Sertoli cells support sperm development
  • Testosterone production
    • Leydig cells


Radiation Therapy (RT)

The germinal epithelium is:

  • Very sensitive to damage from RT
    • 1-1.2 Gy can impair spermatogenesis
    • 3-12 Gy can cause permanent azoospermia (however, recovery is possible by 48 months post RT)
    • Radiation doses of over 6 Gy to the testes are very likely to be associated with infertility
    • Residual sperm may have increased fragmentation

Testicular radiation can cause:

The degree of damage depends on:

  • RT Treatment field placement (close to or including the testicles)
  • Total dose and fractionation schedule

The mechanism of damage appears to be:

  • Destruction of the proliferating germ cell pool
  • Inhibition of differentiation of surviving germ cells


Leydig Cells

Leydig cells are more resistant to RT

  • Dysfunction caused by >20 Gy in prepubertal boys
    • This means that radiation doses > 20 Gy can cause testosterone deficiency.
  • Dysfunction caused by >30 Gy in mature males

RT to the testes can cause:

  • Transient rise in LH with no change in testosterone
  • Elevated LH with decreased testosterone


Clinical impact of impaired leydig cell function and reduced testosterone levels:

  • Failure to progress to puberty
  • Reduced bone mineral density
  • Decreased energy
  • Poor libido
  • Increased incidence of anxiety and depression
  • Altered body composition



Androgen (testosterone) supplementation



Damage to germinal cells was first recognized by Spitz in 1948.

  • Autopsies were done on 30 men who had received nitrogen mustard
  • Complete absence of spermatogenesis in 90%

Since then numerous agents identified that cause testicular damage.

Table: Gonadotoxic chemotherapeutic agents in males:

High risk

Moderate risk

Alkylating agents

    • Procarbazine
    • Cyclophosphamide (>7.5g/m2)
    • Ifosfamide
    • Nitrosoureas (CCNU, BCNU)
    • Melphalan
    • Busulphan (>600mg/m2)

Platinum agents







Germinal epithelium is very sensitive to chemotherapy.

Impact of chemo on testes varies widely:

  • oligozoospermia
  • azoospermia

Extent of damage depends on:

  • Age (prepubertal testes ? Protective)
    • The pre-pubertal testes is less vulnerable to damage than post-pubertal – but damage can still occur.
  • Agent
    • High risk with alkylating agents
    • With multiple agents the toxicity may be synergistic
    • Contribution of each agent may be difficult to determine
  • Dose (higher infertility with higher cumulative doses)
  • Disease itself (controversial)

The extent of damage depends on the agent (alkylating agents are very damaging) and the dose given.

Combination chemotherapy can be very damaging – for example COPP chemotherapy (contains alkylating agents procarbazine and cyclophosphamide) used in the treatment of Hodgkin lymphoma results in permanent azoospermia in 85% of patients.  The ABVD regime which does not contain an alkylating agent is much less damaging with temporary azoospermia in 33% of patients with full recovery in the next 18 months (however this regime contains Adriamycin and so there is an increased risk of cardiotoxicity instead). Hybrid regimes have been developed to treat Hodgkin lymphoma which alternate ABVD with an alkylating agent containing regime to reduce the overall dosage of one particular agent.

Childhood Cancer Survivor Study: Survey of survivor (male) and sibling cohorts7. Reduced fertility was associated with:

  • Radiation therapy of more than 7.5 Gy to the testes
  • Higher cumulative alkylating agent dose (AAD) score
  • Treatment with cyclophosphamide or procarbazine

Leydig cells are rarely affected by chemotherapy (high cumulative doses only).

  • Secondary sex characteristics usually develop normally in boys, despite compete absence in sperm production. 



  • Orchiectomy for treatment of testicular cancer
    • Can cause infertility and low testosterone
  • Radical retroperitoneal lymph node dissection
    • Can cause dry ejaculation or erectile dysfunction
  • Radical prostatectomy
    • Causes erectile dysfunction in 30-80% of patients



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