CYP19 and ESR2 polymorphisms as potential culprits in cryptorchidism

Introduction

Cryptorchidism impairs sperm development and increases the risk of infertility and testicular cancer. Estrogen signalling is critical for proper descent of the testicles, and hormonal imbalances play a role in cryptorchidism. CYP19, also known as aromatase, encodes an enzyme that converts testosterone, a male sex hormone, into estradiol, the main form of estrogen. While estrogen receptors can be activated by estrogen, CYP19 plays an important role in regulating local estrogen levels in tissues such as the testes, as it affects cellular processes controlled by estrogen receptors.

Objective

We aimed to investigate the relationship between polymorphisms in the CYP19 (rs2414096) and ESR2 (rs4986938) and susceptibility to cryptorchidism.

Study design

We genotyped CYP19 (rs2414096) and ESR2 (rs4986938) polymorphisms using PCR-RFLP in DNA isolated from blood samples of cryptorchid children (n = 41) and healthy controls (n = 42). The differences in genotype and allele frequencies between the cryptorchidism and control groups were calculated using the chi-square (χ2).

Results

In cryptorchidism patients, genotypes (p < 0.05) and allele frequencies (p < 0.05) of CYP19 (rs2414096) and ESR2 (rs4986938) polymorphisms showed significant differences compared to controls. CYP19 (rs2414096) and ESR2 (rs4986938), the AA genotype and A allele frequency may be risk factors for cryptorchidism, while the GG genotype and G allele may be protective against cryptorchidism.

Discussion

Our study provides compelling evidence for a significant association between polymorphisms in the CYP19 (rs2414096) and ESR2 (rs4986938) polymorphisms and cryptorchidism susceptibility. These findings extend previous research implicating genetic factors in testicular descent but go further by identifying specific polymorphisms associated with increased risk. While previous studies have suggested a role for estrogen imbalance in cryptorchidism, our results provide concrete genetic evidence supporting this hypothesis. The relatively small sample size necessitates replication in larger cohorts to further validate our findings. Additionally, functional studies are warranted to elucidate the precise mechanisms by which these genetic variants influence cryptorchidism risk. Despite these limitations, our results represent a significant step in unravelling the complex aetiology of this common birth defect.

Conclusion

Our findings show that polymorphisms in CYP19 (rs2414096) and ESR2 (rs4986938), which play a role in estrogen production, are significantly associated with cryptorchidism susceptibility, highlighting the potential role of estrogen pathway variations in testicular descent.

Summary table. Genotype and allele frequencies for CYP19 rs2414096 and ESR2 rs4986938 polymorphisms.

Genotype/Allele	Control (n = 41) n (%)	Case (n = 42) n (%)	pa	OR (95 % (CI)
CYP19 (rs2414096)
Genotype
GG	30 (73.2)	15 (35.7)	0.002	Reference 0.229 (0.089–0.590)
GA	11 (26.8)	24 (57.1)
AA	0 (0)	3 (7.1)
Allele
G	71 (86.6)	54 (64.3)	0.001	Reference 0.279 (0.128–0.606)
A	11 (13.4)	30 (35.7)
ESR2 (rs4986938)
Genotype
GG	34 (82.9)	26 (61.9)	0.041	Reference 0.446 (0.154–1.291)
GA	7 (17.1)	12 (28.6)
AA	0 (0)	4 (9.5)
Allele
G	75 (91.5)	64 (76.2)	0.008	Reference 0.299 (0.119–0.752)
A	7 (8.5)	20 (23.8)

a

Pearson chi-square test. Bold values denote statistical significance at the p < 0.05 level.