Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients

Eric P Allain,David Simonyan,Michaela Gruber,Chantal Guillemette,Trang Le,Patrick Caron,Katrina Vanura,Véronique Turcotte,Karin Venzl,Eric Lévesque

doi:10.1007/s00277-018-3356-z

Abstract

Chronic lymphocytic leukemia (CLL) is not considered a hormone-regulated cancer although sex is a recognized risk factor with men more frequently diagnosed and developing progressive disease. We hypothesized that variable hormonal exposure may have a sexually dimorphic influence on treatment-free survival (TFS). In 156 CLL cases, we quantitatively profiled 29 circulating steroids (progesterone, adrenal precursors, androgens, estrogens, and catechol estrogens) as well as luteinizing hormone (LH) and follicle-stimulating hormone. Median TFS was shorter for men than that for women (80.7 vs. 135.0 months, P = 0.033). Circulating hormone profiles in CLL patients were significantly different from those of healthy donors. In male CLL cases, higher LH levels were associated with shorter TFS (adjusted hazard ratio (HRadj) 2.11; P = 0.004). In female CLL cases, high levels of the potent androgens testosterone and dihydrotestosterone and the sum of methoxy estrogens were associated with an improved TFS with HRadj values of 0.24 (P = 0.007), 0.54 (P = 0.023), and 0.31 (P = 0.034), respectively. Reduced TFS was observed for women with CLL exhibiting high expression of the steroid-inactivating UGT2B17 enzyme. This study is the first to establish a link between the outcome of CLL patients, sex steroids, and pituitary hormones, revealing a sex-specific hormonal imbalance associated with disease progression.

Highlights

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia characterized by an accumulation and clonal proliferation of mature CD5+ B lymphocytes in peripheral blood, bone marrow, and lymphoid organs
Levels of hormones in CLL patients differ by sex and from those of healthy donors Hormone levels below the limit of quantification and detected in less than 10% of cases were excluded from the subsequent analysis
We report a comprehensive profiling of circulating sex steroids and pituitary hormones in men and women with CLL, revealing a sex-specific association of these signaling molecules to treatment-free survival

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia characterized by an accumulation and clonal proliferation of mature CD5+ B lymphocytes in peripheral blood, bone marrow, and lymphoid organs. CLL, leading to vast differences in disease progression, response to treatment, and risk of relapse, with clinical stage, cytogenetic abnormalities, and mutational status of IGHV being the most important prognostic markers [1]. Men develop progressive disease and resistance to treatment more frequently than women who have better prognosis independently of age and CLL stage, and respond better to therapy [2, 4]. CLL is not considered a hormoneregulated cancer but the sexual dimorphism associated with CLL incidence, prognosis, and response to therapy, in addition to what is known regarding the importance of sex hormones for development and function of the immune system, led to the speculation of a potential protective role for these molecules, most estrogens, in hematologic malignancies [5, 6]. Sex-specific somatic alterations in the non-pseudoautosomal and pseudoautosomal regions on chromosomes X and Y have been discussed, [4, 7] in-depth data are still lacking

Methods

Results

Conclusion