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Inhibitory action on GHRH-induced GH secretion of chronic tamoxifen treatment in breast cancer
De Marinis1, Mancini1, Izzi1
1Institutes of, Endocrinology,Internal Medicine and Geriatrics, Clinical,Biochemistry,Clinical Surgery, Catholic University School of Medicine, Rome;,Eli-Lilly, Florence, Italy.
Objective:
Previous in vitro and in vivo studies on animal models have demonstrated that tamoxifen (TAM) inhibits GH secretion. Studies in humans are conflicting. The aim of this study was to evaluate the effect of chronic TAM treatment on GH secretory dynamics in the presence of negligible endogenous oestrogens, in postmenopausal women with breast cancer.
Patients:
Ten female patients were studied over a 6-12-month period after surgical therapy, before medical therapy, and during chronic treatment with TAM (20 mg/day p.o.).
Measurements:
In all subjects we performed a standard GHRH-test (50 mg i.v. as a bolus) and compared the single time points, the peak response and the areas under the curves (AUC), before and during treatment. In basal samples, we evaluated the circulating levels of IGF-1, IGF-BP3 and their ratio, SHBG, FSH, LH, Oestradiol (E2) and PRL. GH was assayed by Immunoradiometric assay (IRMA). Insulin-like growth factor type I (IGF-I), Insulin-like growth factor-binding protein-3 (IGF-BP3), FSH, LH and PRL were measured by Radioimmunoassay (RIA). SHBG was measured by a noncompetitive liquid phase immunoradiometric assay, while E2 was measured directly in plasma by a liquid phase technique.
Results:
TAM chronic treatment significantly reduced GH response to GHRH at single time point evaluations, GH peak response (mean decrease: 59.8 ± 7.3%) and GH-AUC (mean decrease 53.8 ± 8.9%). TAM also significantly reduced plasma IGF-1 levels. No significant variations were found in IGF-BP3 levels or in the IGF-1/IGF-BP3 ratio. A significant inverse correlation between SHBG and IGF-1 circulating levels was noticed during TAM treatment.
Conclusions:
Our data show that long-term tamoxifen treatment blocks the response of GH to exogenous GHRH and reduces IGF-1 levels, possibly by a central mechanism other than the demonstrated peripheral action. The results of this study, keeping in mind the demonstrated mitogenic role of IGF-1 in cancer proliferation, can contribute to clarify the mechanism by which TAM exerts its antiproliferative effect.
Insights
Tamoxifen (TAM) significantly reduces growth hormone (GH) secretion and insulin-like growth factor-1 (IGF-1) levels in postmenopausal women. This tamoxifen effect may contribute to its antiproliferative action in breast cancer treatment.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Previous studies suggest tamoxifen (TAM) inhibits growth hormone (GH) secretion, but human data are conflicting.
- TAM is a widely used treatment for breast cancer, particularly in postmenopausal women.
Purpose of the Study:
- To evaluate the effect of chronic TAM treatment on GH secretory dynamics in postmenopausal women with breast cancer.
- To assess changes in GH, insulin-like growth factor-1 (IGF-1), and related markers during TAM therapy.
Main Methods:
- Ten postmenopausal breast cancer patients were studied before and during 6-12 months of chronic TAM treatment (20 mg/day).
- Growth hormone-releasing hormone (GHRH) tests were performed to assess GH response (peak and area under the curve).
- Circulating levels of IGF-1, IGF-binding protein-3 (IGF-BP3), SHBG, FSH, LH, estradiol, and prolactin were measured.
Main Results:
- Chronic TAM treatment significantly reduced GH peak response (59.8%) and GH area under the curve (53.8%) following GHRH stimulation.
- Plasma IGF-1 levels were significantly decreased by TAM treatment.
- No significant changes were observed in IGF-BP3 levels or the IGF-1/IGF-BP3 ratio. An inverse correlation between SHBG and IGF-1 was noted.
Conclusions:
- Long-term tamoxifen treatment effectively blocks GH response to GHRH and lowers IGF-1 levels in postmenopausal women.
- These effects may be mediated by a central mechanism, potentially contributing to TAM's antiproliferative action in cancer.
- Reduced IGF-1, a mitogen for cancer cells, may be a key factor in tamoxifen's therapeutic efficacy.
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