What are the causes of hypogonadism (low sex hormone production) in patients with germ cell tumors?

Causes of Hypogonadism in Germ Cell Tumors

Hypogonadism in germ cell tumor patients results from multiple mechanisms including pre-existing testicular dysfunction, treatment-related Leydig cell damage from chemotherapy and radiation, and surgical removal of testosterone-producing tissue via orchiectomy. 1, 2

Pre-Treatment Causes

Intrinsic Testicular Dysfunction

• Patients with testicular germ cell tumors have altered hypothalamic-pituitary-gonadal axis function even before any treatment begins, with non-seminoma patients showing particularly blunted FSH and LH responses to GnRH stimulation compared to healthy controls 3
• Leydig cell dysfunction can occur in both the affected testicle and the contralateral (unaffected) testicle prior to any intervention 1
• Testicular microlithiasis is a strong predictor of hypogonadism, increasing the odds ratio for biological hypogonadism at baseline (OR 11) and persisting through long-term follow-up 2
• Biological hypogonadism is present at baseline (before treatment) in approximately 45-51% of germ cell tumor patients 4, 2

Treatment-Related Causes

Surgical Causes

• Unilateral orchiectomy generally preserves normal testosterone levels in most men as the remaining testicle compensates through increased production, though 12-16% of long-term survivors still develop hypogonadism 1
• Bilateral orchiectomy results in permanent, complete testosterone deficiency requiring lifelong hormone replacement therapy 5, 1
• Organ-preserving surgery for testicular intraepithelial neoplasia (TIN) may impair Leydig cell function and requires regular testosterone monitoring 5

Chemotherapy-Induced Damage

• Higher-dose chemotherapy (3-4 cycles) significantly increases the risk of hypogonadism, with odds ratios of 22 at 6 months and 5.8 at 12 months post-treatment 2
• Platinum-based chemotherapy causes direct Leydig cell toxicity, with 51% of patients treated with surgery plus chemotherapy developing biochemical hypogonadism 4
• The combination of chemotherapy and radiation causes more extensive Leydig cell damage than either modality alone, which is why radiation treatment should be postponed in patients scheduled for chemotherapy 5

Radiation-Induced Damage

• Radiation therapy at 20 Gy (the standard dose for TIN treatment) impairs Leydig cell function, requiring regular serum testosterone monitoring after treatment 5
• Adjuvant radiotherapy temporarily increases the odds ratio for biological hypogonadism at 6 months (OR 10) and 12 months (OR 3.9) 2
• Scattered radiation from treating one testicle can damage the contralateral unaffected testicle, which is why orchiectomy is preferred over radiation when a normal contralateral testicle exists 5

Secondary Hormonal Effects

Elevated Gonadotropins Causing False β-hCG Elevation

• Iatrogenic hypogonadism from treatment causes secondary elevations of LH and FSH, which can cross-react with β-hCG radioimmunoassays and produce spurious elevations (1.7-7.8 mIU/ml) that may be mistaken for disease recurrence 6
• This is particularly important because the NCCN guidelines note that mildly elevated β-hCG (generally <20 IU/L) can result from hypogonadism and should not trigger treatment decisions without further workup 5
• Administration of exogenous testosterone normalizes LH, FSH, and the spuriously elevated β-hCG levels 6

β-hCG-Secreting Tumors Causing Hypergonadism

• In rare cases, β-hCG-secreting germ cell tumors (particularly intracranial tumors) can cause hypogonadotropic hypergonadism rather than hypogonadism, as β-hCG has LH-like activity that stimulates testosterone production 7

Clinical Implications

Monitor serum testosterone, LH, and FSH levels at baseline before orchiectomy and regularly during follow-up, especially in the first year after treatment when hypogonadism risk is highest 5, 1, 2

Key predictive factors for post-treatment hypogonadism include:

• Biological hypogonadism at baseline (strongest predictor with OR 53-125 across follow-up timepoints) 2
• Testicular microlithiasis (OR 3.0-5.4 at various timepoints) 2
• Receipt of higher-dose chemotherapy or radiotherapy 2

All patients with subnormal testosterone levels and clinical signs of androgen deficiency should be offered hormone replacement treatment 5