Commentary on “Testis tissue cryopreservation may be considered in boys with cryptorchidism”

Dear Editor, I would like to congratulate Mamsen et al.1 on their extensive and scientifically valuable work. I analyzed their raw data presented in Table 1 of the original article from a different perspective and discovered an effect not mentioned in the article. My analysis showed that luteinizing hormone (LH) levels are significantly lower in patients at high infertility risk (HIR), whose testes lack A dark (Ad) spermatogonia and display an abnormal ratio of germ cells per cross-sectional tubule (G/T), compared to patients at low infertility risk (LIR; G/T >0.6 and Ad >0.005) with P = 0.023 (Figure 1). In practice, we categorize boys into the HIR group when Ad spermatogonia are absent due to impaired mini-puberty.2 The results reported by Mamsen et al.1 confirm our previous findings of hypogonadotropic LH levels in patients with HIR and underline the importance of histologically determining the number of testicular Ad spermatogonia as a key prognostic marker for adult fertility.2–5 Patients with the most severe impairment of mini-puberty and whose gonocytes do not differentiate into Ad spermatogonia have the highest risk of infertility.4,5Figure 1: Hormone levels in testicular samples from HIR/LIR patients. Median FSH and LH levels and LH/FSH ratios are plotted against 21 samples from HIR and 18 samples from LIR cryptorchid boys. Wilcoxon-Mann-Whitney test was performed. P values are given at the top. HIR: high infertility risk; LIR: low infertility risk; FSH: follicle-stimulating hormone; LH: luteinizing hormoneAt the molecular level, testicular samples from boys with cryptorchidism and HIR show abnormally low expression of most genes essential for the function of the hypothalamus–pituitary–testicular axis.6 Notably, the expression of early growth response 4 (EGR4), a gene involved in regulating LH secretion, is almost undetectable.6 We have previously demonstrated that the development of Ad spermatogonia depends on LH and testosterone.7 Given that EGR4 is pivotal for LH secretion, these results provide additional evidence that EGR4 is important for the formation of Ad spermatogonia and that the LH–testosterone axis is involved in this developmental process.6 This observation challenges the current dogma that the undescended position of the cryptorchid testis alone causes adult infertility. Furthermore, a unique long-term, prospective, and follow-up study over 20 years showed that sperm concentrations correlate with the number of Ad spermatogonia observed at the time of orchidopexy.5 In that study, all males in the HIR group (bilateral absence of Ad spermatogonia) were at least oligospermic (median: 4.1 × 106 sperm per ejaculate) and 20% were found to be azoospermic. The correlations between testicular histology and postpubertal hormone levels confirm a relative gonadotropin deficiency in most males with cryptorchidism.5 Therefore, the low LH levels in patients with HIR reported by Mamsen et al.1 provide additional evidence that Ad spermatogonia is a critical discriminating biomarker for fertility outcomes in cryptorchidism. COMPETING INTERESTS The author declares no competing interests.