Selpercatinib Causes Hypogonadism and Infertility in Most Treated Men
Nearly all male MTC patients on selpercatinib developed erectile dysfunction within 1 month, with lab evidence of HPG axis disruption and near-universal azoospermia.
Summary
A new study from Pisa found that selpercatinib, a targeted RET inhibitor used in advanced medullary thyroid cancer, severely disrupts the male hormonal axis. Among 19 men treated with the drug, 94.7% experienced erectile dysfunction, typically within just one month of starting therapy. Over the first year, FSH rose significantly by roughly 62%, signaling testicular damage. In men followed beyond 24 months, LH and SHBG also rose while total and free testosterone dropped meaningfully. Semen analysis in 6 patients revealed azoospermia in 5 and severe oligospermia in 1. These findings suggest that selpercatinib damages Sertoli and Leydig cells — the testicular cells responsible for sperm production and testosterone secretion — leading to functional hypogonadism. The authors recommend hormonal evaluation and fertility counseling for men before starting this treatment.
Detailed Summary
Targeted cancer therapies are transforming outcomes in rare malignancies, but their off-target hormonal effects remain poorly characterized. This study draws attention to a significant and underappreciated consequence of selpercatinib — a highly selective RET kinase inhibitor approved for advanced medullary thyroid carcinoma (MTC) — on the male reproductive endocrine axis.
Researchers at Pisa University Hospital prospectively evaluated 19 men with advanced MTC before and after 12 months of selpercatinib therapy, monitoring FSH, LH, total and free testosterone, and SHBG. A subset of 7 patients (37%) was followed beyond 24 months. Semen analysis was performed in 6 patients.
The results were striking. Erectile dysfunction affected 94.7% of patients, with 88.9% developing it after starting selpercatinib, typically within the first month. Over the first year, FSH rose by 61.9% — a marker of primary testicular damage. In those followed longer, FSH rose 60.6%, LH by 20.5%, and SHBG by 27.7%, while total testosterone fell 20% and free testosterone dropped 12.5%. Of the 6 men who underwent semen analysis, 5 had azoospermia and 1 had severe oligospermia — outcomes indicating profound impairment of sperm production.
These patterns collectively indicate damage to both Sertoli cells (which support sperm maturation) and Leydig cells (which produce testosterone), producing a picture of hypergonadotropic hypogonadism. The mechanism may relate to RET receptor signaling in gonadal tissue, though this remains to be fully elucidated.
For clinicians and patients, the implications are substantial. Men of reproductive age contemplating selpercatinib therapy should be offered fertility counseling and potentially sperm banking before treatment initiation. Hormone replacement therapy may be appropriate for symptomatic hypogonadism. Limitations include the small sample size, lack of a control group, and the summary being based solely on the published abstract.
Key Findings
- 94.7% of men on selpercatinib developed erectile dysfunction, typically within 1 month of starting treatment.
- FSH rose ~62% over 12 months, indicating primary testicular damage to Sertoli cells.
- Long-term users showed 20% drop in total testosterone and 12.5% drop in free testosterone.
- 5 of 6 men who underwent semen analysis had azoospermia; 1 had severe oligospermia.
- Authors recommend baseline HPG axis testing and fertility counseling before starting selpercatinib.
Methodology
Prospective evaluation of 19 men with advanced MTC at a single Italian center, measuring reproductive hormones before and after 12 months of selpercatinib; 7 patients were followed beyond 24 months. Semen analysis was conducted in 6 of 19 participants. No control group was included.
Study Limitations
The study enrolled only 19 patients at a single center without a control group, limiting generalizability. Full semen analysis was available in only 6 men. The summary is based on the abstract only, as full text was not accessible.
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