Why does bosentan (endothelin receptor antagonist) cause oligospermia in a male patient with pulmonary arterial hypertension and tumor lysis syndrome?

Why Bosentan Causes Oligospermia

Bosentan and other endothelin receptor antagonists as a class are capable of causing testicular atrophy and male infertility through their mechanism of blocking endothelin receptors that play a role in testicular function. 1

Mechanism of Testicular Toxicity

The concern for oligospermia with bosentan stems from the drug's class effect on the endothelin system in testicular tissue:

• Endothelin receptors (both ET-A and ET-B) are present in testicular tissue and appear to play a role in normal spermatogenesis and testicular function. 1
• Bosentan is a dual endothelin receptor antagonist that blocks both ET-A and ET-B receptors systemically, including in the testes. 1, 2
• Blockade of these receptors in testicular tissue can lead to impaired spermatogenesis, testicular atrophy, and reduced sperm production. 1

Clinical Evidence and Guideline Recommendations

The major cardiology guidelines specifically address this reproductive toxicity:

• The ACCF/AHA 2009 Expert Consensus Document explicitly states that "endothelin antagonists as a class may be capable of causing testicular atrophy and male infertility." 1
• The European Society of Cardiology 2004 guidelines similarly warn that "endothelin antagonists as a class may be capable of causing testicular atrophy and male infertility." 1
• The CHEST 2004 guidelines echo this concern, stating "endothelin antagonists as a class may be capable of causing testicular atrophy and male infertility." 1

Mandatory Counseling Requirements

All guidelines mandate that younger males who may consider conceiving should be counseled regarding this possibility prior to taking these drugs. 1

This counseling requirement reflects:

• The potential for permanent or prolonged effects on fertility 1
• The need for informed decision-making before initiating therapy in men of reproductive age 1
• The class-wide nature of this effect (not unique to bosentan but shared by all endothelin receptor antagonists) 1

Important Clinical Context

This testicular toxicity concern is distinct from the teratogenicity risk in females—it represents direct gonadal toxicity in males rather than fetal harm. 1

The oligospermia risk should be weighed against the mortality benefit of bosentan in pulmonary arterial hypertension, where the drug has demonstrated:

• Improved survival rates (97% at 1 year, 91% at 2 years in functional class III IPAH) 1
• Reduced pulmonary vascular resistance and improved exercise capacity 1
• Benefits in time to clinical worsening 1

For men with PAH who desire future fertility, this reproductive toxicity must be discussed before starting bosentan, but the life-threatening nature of untreated PAH typically necessitates proceeding with therapy despite this risk. 1