Abstract: Endocrine treatment represents the cornerstone of endocrine-sensitive premenopausal early breast cancer. The estrogen blockade plays a leading role in the therapeutic management of hormone receptor-positive breast cancer together with surgery, radiotherapy, and selective antiestrogen treatments. For several years, selective estrogen receptor modulators, such as tamoxifen, have represented the mainstay of therapy. The role of amenorrhea has been extensively elucidated in the past year: the benefit observed with chemotherapy-induced amenorrhea has strengthened its therapeutic role. Luteinizing hormone-releasing hormone (LHRH) has been introduced in oncology practice to induce amenorrhea in order to increase the advantage obtained from endocrine treatment. Triptorelin is one of the most widely used LHRH analogs currently available in clinical practice. It was recently investigated in two major clinical trials that studied the role of complete estrogen blockade in the premenopausal setting. Both showed the clinical benefit due to ovarian suppression treatment, primarily in high-risk patients. Furthermore, triptorelin and other LHRH analogs have recently been investigated in the attempt to preserve the ovarian function in young patients. The medical treatment of early breast cancer is always evolving in the effort to search for safe and efficacious treatments. The role of LHRH analogs is actually well recognized as contributing to the improvement of the medical treatment of premenopausal women with early breast cancer.
Keywords: adjuvant, hormone therapy, LHRH, amenorrhea
Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hypo-physiotropic hormone produced by the hypothalamic neurons, which plays a central role in the endocrine regulation and the control of reproductive functions. It is secreted, in a pulsatile way, from the median eminence into the portal vein system, reaching the anterior pituitary gland inducing the release of the following two gonadotropin hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The role of FSH and LH is crucial in the gametogenesis and steroid production. The gonadal steroids regulate the secretion of LHRH through the binding to specific receptors expressed on the hypothalamic neuronal cells and pituitary gland.1 Since its discovery, LHRH has been studied for its potential activity in controlling the growth of endocrine sensitive cancer cells such as prostate, ovarian, endometrial, and breast cancers. The following two types of LHRH analogs have been developed: the LHRH agonists and the LHRH antagonists. LHRH agonists were introduced initially in the treatment of endocrine-sensitive cancers, such as prostate and premenopausal breast cancers. They represent the cornerstone of current endocrine treatments for both early and advanced disease. LHRH antagonists were developed some years later; their main application is in the management of prostate cancer.
LHRH agonists: biology and antitumoral effect
The LHRH agonists used in daily clinical practice are as follows: goserelin, tryptorelin, leuprorelide, and buserelin. They are decapeptides with an arginine in position 8 (Arg8) that is essential for the affinity to the mammalian receptor. The introduction of hydrophobic groups on the sixth amino acid further increases this bond with a major resistance to the enzymatic degradation.2 The LHRH analogs operate as anticancer agents suppressing the pituitary gonadal functions, determining the fall of gonadal steroids levels, and reducing their mitogenic activity. Furthermore, it seems that LHRH analogs could have a direct antitumoral effect. In fact, the LHRH receptors are present in the cancer cells. The mRNA encoding for these receptors is similar to the pituitary receptors. An inhibition in cellular tumor growth has been observed in breast cancer.3–10 Physiologically, in pituitary gland, the gonadotropin receptor (GnRH) signaling is mediated through the G-protein αq. These proteins conduct the subsequent activation of phopholipase C (PLC) that catalyzes the hydrolysis of membrane phospholipids generating the liberation of intracellular Ca2+.11,12
The antiproliferative effect of LHRH analogs seems to be related to the signal transduction pathways involving the growth factor-induced mitogenic signaling, as the activity of MAPK and the c-fos expression. The GnRH receptors evident in the tumor activate phosphotyrosine phosphatase (PTP), resulting in the inhibition of mitogenic signal transduction and the reduction of cell proliferation.13Normally, estrogen induces gene transcription through nuclear receptor activation binding to the promoter of sensitive genes, but other unconventional transcriptional pathways could be involved as follows: steroidogenic factor-1 (SF-1),14 specific factor-1 (Sp1),15–17 nuclear factor-Y (42), and activator protein-1 (AP-1).18,19 Furthermore, the MAPK pathway may be involved in a nongenomic stimulus, inducing the activation of proto-oncogene c-fos.20