Introduction

Renal cell carcinoma (RCC) is a common malignant tumor derived from renal parenchyma. As the third most common malignant tumor of the adult urinary system, it accounts for about 5% of all adult malignant tumors1, and it tends to occur between 50 and 70 years old, among which RCC accounts for about 90%. With the popularization of B-ultrasound and CT imaging in recent years, the incidence of RCC is increasing year by year. Surgical resection of the tumor is currently the only way to cure RCC. However, nearly one-third of patients with RCC still have recurrence or distant metastasis after surgical treatment2. In recent years, systemic therapy has improved the overall survival of advanced RCC, but the median progression-free survival is also limited, and the long-term prognosis is poor. Therefore, the mechanism of the occurrence and progression of RCC still needs to be further studied in order to provide a new scheme for the treatment of RCC.

Like most tumors, the etiology of renal cell carcinoma is complex and not yet fully clasified. Only 2 − 4% of renal cell carcinomas have a clearly identified cause, such as Von Hippel-Lindau (VHL) disease, which is a common hereditary form of renal cell carcinoma. Epidemiological studies have found that there is a significant gender difference in the incidence of RCC, and the male to female ratio is about 2:1. Gender, smoking, obesity and hypertension are independent risk factors for RCC3,4. However, the gender difference in the incidence of RCC gradually disappeared after the age of 705. At the same time, studies have found that the cancer-specific mortality rate of premenopausal female patients with RCC is significantly lower than that of male patients of the same age, but the cancer-specific mortality rate of postmenopausal female patients is not significantly different from that of male patients of the same age6,7. Therefore, the difference in sex hormone levels may be an important reason for the difference in incidence and prognosis of patients with clear cell renal cell carcinoma(ccRCC) between different genders. The aim of this study is to explore the role of sex hormones in the occurrence and development of ccRCC by retrospectively analyzing the difference of sex hormone levels between male patients with ccRCC and with simple renal cysts.

Study patients and methods

Patients

The clinical data of male patients with ccRCC and simple renal cyst who underwent surgical treatment in our hospital from 2017 to 2023 were collected. All patients had definite pathological diagnosis after surgery. Inclusion criteria: ①. Age > 18 years old male; ② Male patients with ccRCC and simple renal cyst with definite pathological diagnosis after surgery. Exclusion criteria: ①. Patients with incomplete clinical data; ②. Take medication that may affect sex hormone levels;③. Patients with severe uncontrolled comorbidities including cardiopulmonary disease, endocrine disease, renal failure ;④. Patients with other kinds of cancer. A total of 56 male patients with ccRCC and 82 male patients with simple renal cyst were included in the study. Among them,10 patients with ccRCC were grade I (classified according to the four-tiered WHO/ISUP grading system), 25 were grade II, 11 were grade III, 3 were grade IV, and 7 were ungraded. All the procedures performed were approved by the institutional review boards of the Ruijin Hospital Lu Wan Branch Ethics Committee. All methods were carried out in accordance with relevant guidelines and regulations. informed consent was obtained from all subjects.

Data statistics and analysis

The clinical data collected mainly included patients’ age, height, weight, BMI, serum luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), prolactin (PRL), progesterone (P) and testosterone (T).

Continuous data were subjected to the Kolmogorov-Smirnov test before analysis to determine whether these data followed a normal distribution. The data with normal distribution and homogeneity of variance (E2, body weight, BMI) were analyzed by independent sample t test, and the data with abnormal distribution or (and) heterogeneity of variance (age, FSH, LH, PRL, P, T) were analyzed by rank sum analysis. Logistic regression was used to analyze the relationship of Age, FSH, E2 with ccRCC. Continuous variables were expressed as Mean ± SD.

Results

Analysis of differences clinical data between patients with ccRCC and patients with simple renal cyst

The age, height, weight, BMI, serum LH, PRL, P, and T of patients with ccRCC were 58.57 ± 12.19 years,1.70 ± 0.05 m,73.39 ± 9.58 kg,25.09 ± 2.99 kg/m2,5.97 ± 3.22mIu/ml,12.34 ± 6.06ng/ml,0.55 ± 0.38ng/ml, 3.64 ± 1.08 ng/ml respectively; Compared with simple renal cyst patients, age (61.79 ± 10.39 years old), height (1.71 ± 0.06 m), weight (73.43 ± 11.26 kg), BMI (24.83 ± 3.19 kg/m2), serum LH (6.69 ± 5.20mIu/ml), PRL (11.85 ± 6.66ng/ml), P (0.52 ± 0.54ng/ml), and T (3.74 ± 1.50ng/ml). The difference was not statistically significant. The levels of serum FSH and E2 in patients with ccRCC were 9.33 ± 8.23 mIu/ml and 28.91 ± 10.95pg/ml, respectively, which were significantly lower than those in patients with simple renal cysts (12.26 ± 11.18 mIu/ml and 34.48 ± 15.90pg/ml). The differences were statistically significant (p = 0.002, p = 0.024, respectively) ( Table-1).

Table 1 Differences clinical data between male patients with CcRCC and male patients with simple renal cyst.
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Correlation analysis of E2, FSH and ccRCC

Logistic regression analysis showed that age, height, weight, BMI, LH, FSH, PRL, P, T were not significantly correlated with ccRCC. The level of serum E2 was an influencing factor of ccRCC, and was negatively correlated with ccRCC (OR = 0.968, p = 0.027) ( Table-2).

Table 2 Logistic regression analysis of the relationship between age, E2, FSH and CcRCC.
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Relationship between serum E2, FSH and pathological grade of ccRCC

The serum E2 of patients with pathological grade I (n = 10), grade II (n = 25), grade III (n = 11) and grade IV (n = 3) were 29.23 ± 6.23 pg/ml, 30.42 ± 10.90 pg/ml and 26.85 ± 10.07 pg/ml, 37.66 ± 11.15 pg/ml, respectively (Figure-1). There was no significant difference between groups (p = 0.40). The serum FSH of patients with pathological grade I, II, III and IV of ccRCC were 6.91 ± 3.59 mIu/ml, 7.88 ± 3.55 mIu/ml, 11.77 ± 10.56 mIu/ml, 6.70 ± 3.85 mIu/ml, respectively (Figure-2). There was no significant difference between the groups (p = 0.58).

Fig. 1
figure 1

Serum E2 of patients with different pathological grades.

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Fig. 2
figure 2

Serum FSH of patients with different pathological grades.

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Discussion

Sex hormones have significant relationships with the occurrence and progression of certain tumors. For instance, estrogen is associated with breast cancer, and testosterone with prostate cancer8. Studies have confirmed that E2 can significantly promote the invasion and metastasis of hormone-sensitive tumors such as breast cancer, endometrial cancer and lung cancer9,10,11, and E2 inhibitors have also been confirmed to be effective on the above-mentioned tumors with positive expression of E2 receptors. The role of E2 in the development and progression of ccRCC has not been elucidated, and the mechanism remains unclear. E2 receptor is a receptor-activated transcription factor. As the target of E2, it mediates the growth regulation of normal and tumor tissues by E2. According to different structures, E2 can be divided into estradiol receptor-α (ER-α) and estradiol receptor-β (ER-β)12. Usually, ER-α mediates E2 to promote tumor progression, while ER-β mediates E2 to inhibit tumor occurrence and antagonizes the effect of ER-α13. Different types of E2 receptors are expressed in different tissues, which mediate different effects of E2. The expression level of ER-α in breast cancer tissue is increased, and the expression level of ER-β is decreased. E2 promotes the occurrence and development of breast cancer through ER-α14,15. However, ER-β is mainly expressed in RCC tissues, and the expression of ER-β in RCC tissues is significantly lower than that in adjacent normal tissues16,17. Therefore, E2 may play a role in inhibiting the invasion and metastasis of RCC through ER-β. ER-β has a cancer suppressive role via reducing the transcriptional factor activity of hypoxia inducible factor − 1α (HIF-1α), whereas ER-α does the opposite18. One study found that E2-activated ER-β not only remarkably reduced growth hormone downstream signaling activation of the AKT, ERK, and JAK signaling pathways but also increased apoptotic cascade activation19. The present study showed that serum E2 levels in patients with ccRCC were significantly lower than those in patients with simple renal cysts, suggesting that E2 may inhibit the occurrence of RCC. The results of logistic regression analysis also indicated that E2 was negatively correlated with clear ccRCC. The serum E2 of patients with pathological grade III ccRCC was lower than that of patients with pathological grade I and II ccRCC, which imply the lower E2 is associated with the higher grade of ccRCC. Due to the sample size of the study is limited, the difference was not statistically significant, but it may still suggest that E2 is negatively correlated with the progression of renal clear cell carcinoma. Furthermore, it implies that ER-β may be a useful prognostic marker for ccRCC progression and a novel developmental direction for RCC treatment improvement.

FSH promotes the growth and maturation of gonadal organs through FSH-receptor (FSHR). FSHR is a G protein-coupled transmembrane receptor. It has been traditionally believed that FSHR is only expressed in testicular Sertoli cells and ovarian granulosa cells in humans and mammals. However, recent studies have found that FSHR is expressed in vascular endothelial cells of many malignant tumors, including prostate cancer, RCC, and urothelial carcinoma. Studies have found that FSH is related to the invasion and metastasis of ovarian cancer and prostate cancer20,21. RCC is a kind of tumor with abundant blood supply and more neovascularization. Studies have found that the expression level of FSHR in vascular endothelial cells of renal clear cell carcinoma tissues is positively correlated with the effectiveness of sunitinib targeted therapy22, suggesting that FSH may be involved in angiogenesis and metastasis of RCC. It has been reported that the binding of FSH to FSHR in ovarian granulosa cells increases the level of hypoxia-inducible factor-1α(HIF-1α) and thus upregulates vascular endothelial growth factor (VEGF)23. VEGF is the target of targeted therapy in ccRCC. This study found that the level of FSH in patients with ccRCC was significantly lower than that in patients with simple renal cysts, suggesting that the serum FSH may promote the invasion and progression of RCC via the overexpression of FSHR in ccRCC tumor tissues. The serum FSH of patients with pathological grade III renal clear cell carcinoma was higher than that of patients with pathological grade I and II ccRCC, which imply the higher FSH may be associated with the higher grade of ccRCC. However, the results of the logistic regression analysis indicated that there was no significant correlation between FSH and ccRCC. Therefore, the relationship between FSH and ccRCC is ambiguous, and a larger sample size study is necessary.

Conclusions

The levels of E2 and FSH in patients with ccRCC are significantly lower than those in patients with simple renal cysts, and E2 is negatively correlated with RCC, suggesting that E2 and FSH may play a role in the occurrence and progression of RCC. The study implied the potential estrogen-based therapeutic strategies in ccRCC and further study is needed to explore its mechanism.