Association between Prolactin/Testosterone Ratio and Breast Cancer in Chinese Women
Breast cancer remains one of the most prevalent malignant tumors worldwide and is the second leading cause of cancer-related deaths globally. The breast is a target organ for various endocrine hormones, which regulate its growth and development. While the roles of estrogen and progesterone in breast cancer have been extensively studied, the relationship between prolactin, testosterone, and breast cancer has recently gained increasing attention. This study aims to explore the association between the prolactin/testosterone (PRL/T) ratio and breast cancer in Chinese women, shedding light on the potential role of these hormones in breast cancer risk.
Background and Rationale
Prolactin is a hormone that binds to prolactin receptors (PRLRs) and plays a crucial role in the development and remodeling of mammary glands. While some studies suggest that high prolactin levels may predispose individuals to breast cancer, the clinical correlation between hyperprolactinemia and breast cancer remains debated. Despite interventions targeting prolactin blockage, a subset of patients still develop breast cancer, indicating that other factors may be at play.
Testosterone, a biologically active hormone, exerts physiological effects on various female organs, including the breasts, by binding to the androgen receptor (AR). Animal studies suggest that testosterone may function as an endogenous mammary protector. However, the association between total testosterone levels and breast cancer remains inconclusive. Unlike estrogen, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone, which fluctuate with the menstrual cycle, prolactin and testosterone levels are relatively stable. This stability makes the PRL/T ratio a potentially useful indicator for assessing breast cancer risk.
Study Design and Methodology
The study protocol was approved by the Ethical Committee of Qilu Hospital of Shandong University, and written informed consent was obtained from all participants. This cross-sectional study included 1461 preoperative inpatients with breast diseases, including breast cancer and benign breast disease, from the Breast Surgery Department of Qilu Hospital between January 2019 and December 2020. Participants were aged 13–90 years, underwent breast surgery with a pathological diagnosis, had no history of using medications to treat hyperprolactinemia in the preceding month, and had no history of androgen treatment or implantation. Participants with missing hormone level data were excluded, resulting in 1340 participants for final analysis.
Post-menopausal status was defined as a time interval of at least one year between data collection and the cessation of menstruation, including patients who had undergone ovariectomy, taken ovarian function suppressants, or experienced menstrual suspension due to other pathological reasons.
Fasting blood samples were collected on the morning following admission. Serum prolactin, FSH, LH, estradiol, progesterone, and testosterone levels were measured using a Roche Cobas e601 analyzer. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m²), and the PRL/T ratio was defined as prolactin (ng/mL) divided by testosterone (ng/dL).
Statistical Analysis
All analyses were performed using R and Empower software. Continuous variables were reported as median values with interquartile ranges, while categorical variables were described using frequencies and proportions. Differences between groups were assessed using the Kruskal-Wallis rank-sum test for continuous variables and Pearson’s chi-squared test for categorical variables.
Three logistic regression models were constructed to investigate the association between the PRL/T ratio and breast cancer. Model 0 was unadjusted, Model 1 was adjusted for age, and Model 2 was adjusted for age, BMI, and marital status. Smooth curves were used to illustrate trends between the PRL/T ratio, prolactin, testosterone levels, and the predicted probability of breast cancer. Stratified analyses were conducted to assess the associations between the PRL/T ratio and breast cancer across various subgroups.
Results
Participant Characteristics
Participant characteristics were categorized based on pre-menopausal and post-menopausal status. Post-menopausal women were generally older, had higher BMI, FSH, LH levels, and a higher proportion of married participants and malignant breast tumors compared to pre-menopausal women. Prolactin, progesterone, estradiol, testosterone levels, and the PRL/T ratio were typically higher in pre-menopausal women.
Univariate and Multivariate Analysis
Univariate logistic regression results showed positive correlations between age and breast cancer in both pre-menopausal and post-menopausal women. BMI tended to be positively related to breast cancer in pre-menopausal women. The odds ratios (ORs) for prolactin, FSH, LH, estradiol, and testosterone were close to 1.00, indicating no significant association. However, the OR for progesterone was higher in post-menopausal women.
In multivariate logistic regression models, the PRL/T ratio was positively associated with breast cancer in pre-menopausal women, although the results were not statistically significant. In post-menopausal women, the correlation between the PRL/T ratio and breast cancer was weaker and also not statistically significant.
Smooth Curve Analysis
Loess-fitted smooth curves illustrated the trends between the PRL/T ratio, prolactin, testosterone levels, and the predicted probability of breast cancer. In pre-menopausal women, there was a linear trend between the PRL/T ratio and the predicted probability of breast cancer. In post-menopausal women, the relationship was non-linear, exhibiting a U-shaped curve. No obvious trend was observed between prolactin levels and breast cancer in pre-menopausal women, but a non-linear increasing trend was found in post-menopausal women. Testosterone levels showed a non-linear U-shaped relationship with breast cancer in pre-menopausal women and a non-linear increasing trend in post-menopausal women.
Stratified Analysis
Stratified analyses revealed that the PRL/T ratio was positively related to breast cancer in pre-menopausal women aged 18–50 years, with normal BMI (18.5–24.0 kg/m²), and lower prolactin levels. However, these results were not statistically significant. In post-menopausal women, the odds of breast cancer related to the PRL/T ratio increased with higher testosterone and BMI levels, although the differences were not significant. No statistically significant interactions were found between age, BMI, prolactin, testosterone, and the PRL/T ratio.
Discussion
Previous studies have shown that hyperprolactinemia is positively correlated with the occurrence of fibroepithelial tumors in benign breast disease. Epidemiological evidence suggests that high serum prolactin levels are significantly associated with an increased relative risk of estrogen receptor-positive (ER+) breast cancer. These findings highlight the strong correlation between prolactin levels and the tumorigenesis and progression of breast cancer.
Testosterone may function as an endogenous mammary protector, but chronic overproduction can lead to increased estrogen levels, which are associated with the development of ER+ tumors. While some epidemiological studies suggest a link between higher testosterone levels and increased breast cancer incidence, others have not found such an association. The evidence remains inconclusive.
In this study, the PRL/T ratio was positively correlated with breast cancer in pre-menopausal women, with an increasing linear trend between the PRL/T ratio and the predicted probability of breast cancer. Although the results were not statistically significant, they may have clinical significance. The PRL/T ratio may be a more appropriate indicator for assessing breast cancer risk in pre-menopausal women than prolactin or testosterone alone, as it counterbalances their respective effects on breast cancer.
Limitations
This study has several limitations. First, the results may not be generalizable to the entire Chinese population. Second, the cross-sectional design only demonstrates an association, not causality, between the PRL/T ratio and breast cancer. Finally, since prolactin is closely related to other sex hormones and testosterone is a primary substrate for estradiol, further analyses are needed to explore the association between the PRL/T ratio and different hormone receptor and molecular types of breast cancer.
Conclusion
The study indicates a positive correlation between the PRL/T ratio and breast cancer, particularly in pre-menopausal women. Although the results were not statistically significant, they suggest that the PRL/T ratio may be a potential indicator for breast cancer screening and improve the efficacy of breast cancer risk prediction. Further research is needed to validate these findings and explore the underlying mechanisms.
doi.org/10.1097/CM9.0000000000002942
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