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Effects of Raloxifene on Prolactin and Estradiol Levels in Premenopausal Women
aloxifene is a selective estrogen receptor modulator (SERM), FDA-approved for the prevention and treatment of osteoporosis. Recently, in the National Surgical Adjuvant Breast and Bowel Project-sponsored Study of Tamoxifen and Raloxifene (STAR) trial, raloxifene was compared with tamoxifen to determine its effect on preventing invasive breast cancer as well as its side effects. Tamoxifen is also a SERM, and the only drug currently FDA-approved for the prevention of breast cancer. The STAR trial showed that both agents reduced invasive breast cancer incidence effectively (by approximately 50%) and that raloxifene treatment was associated with fewer adverse events (Vogel VG et al. JAMA 295: 2727–41, 2006). A limitation of the STAR trial is that the study included only postmenopausal women. No long-term studies of raloxifene in premenopausal women have been conducted, yet this agent is of potential interest in this population. There is a scarcity of knowledge regarding the effects of raloxifene in premenopausal women. Therefore, a phase II trial examining the safety of raloxifene and its effects on bone density, serum hormone levels, and other clinical end points in premenopausal women was led by Jo Anne Zujewski, MD, and Jennifer Eng-Wong, MD, MPH, of the Medical Oncology Branch (MOB/NCI). In this study, premenopausal women at increased risk for breast cancer received raloxifene 60 mg/day for 2 years. This was the first trial to examine the long-term effects of raloxifene on prolactin, sex hormone–binding globulin (SHBG), and estradiol levels in premenopausal women at increased risk for developing invasive breast cancer. Of the 37 women who enrolled, 27 completed 12 months of raloxifene treatment, with 23 providing paired (baseline and 12-month) serum prolactin measurements and 20 providing paired serum estradiol and SHBG measurements. Prolactin levels did not significantly change with raloxifene treatment, but SHBG levels increased (mean change 7.3 nmol/L; P = 0.0001; 95% CI 3.9 to 10.7). Differences between the baseline and 12-month measurements of estradiol were striking when both were taken during the early follicular phase of the menstrual cycle, which was the case for 15 of the 20 women. When the estradiol analysis was restricted to these 15 women, the mean baseline estradiol level for this group was 87 pg/mL (± 50), and the levels were elevated after 12 months on raloxifene (mean change 42 pg/mL; P = 0.048; 95% CI 1 to 84). No significant difference was detected between baseline and posttreatment prolactin levels in the only other study to examine levels of prolactin and estradiol in premenopausal women treated with raloxifene; however, there was a 45% increase in estradiol over the entire menstrual cycle for premenopausal women given 200 mg of raloxifene daily for 28 days (Baker VL et al. J Clin Endocrinol Metab 83: 6–13, 1998). In our study, estradiol levels increased 48%. Therefore, our prolactin and estradiol results are consistent with this prior report, although women in our study received a lower dose of raloxifene (60 mg daily) and were on the drug for a longer period (12 months). In conclusion, it is unclear if the increase in both SHBG and estradiol has physiological consequences or how long the elevated levels persist after cessation of raloxifene treatment. No significant change in the circulating levels of prolactin occurred with raloxifene treatment; however, raloxifene may be able to modulate prolactin signaling in breast tissue through mechanisms that are not reflected in a global measurement of circulating prolactin levels. Tamoxifen has been shown to down-regulate prolactin receptor mRNA expression in the breast tissue of postmenopausal women (de Castillo B et al. Eur J Surg Oncol 30: 515–9, 2004) and to bind directly to the prolactin receptor and inhibit downstream signaling mediated by prolactin (Biswas R and Vonderhaar BK. Endocrinology 128: 532–8, 1991; Das RB et al. Mol Cell Endocrinol 98: 1–8, 1993; and Das R and Vonderhaar BK. Cancer Lett 116: 41–6, 1997). Raloxifene also may modulate the actions of prolactin locally either by regulating prolactin receptor expression or by inhibiting prolactin receptor signaling in breast tissue. Future research using additional specimens collected during this trial and in collaboration with Barbara Vonderhaar, PhD (Chief of the Mammary Biology and Tumorigenesis Laboratory and Head of the Molecular and Cellular Endocrinology Section) will focus on addressing the effects of raloxifene on the local prolactin/prolactin receptor system in breast tissue. |
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