0021-972X/98/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1998 by The Endocrine Society
Vol. 83, No. 5 Printed in U.S.A.
Effect of Tamoxifen on Serum Lipid Metabolism YASUO HOZUMI, MIKIHIKO KAWANO, TSUYOSHI SAITO,
AND
MICHIO MIYATA
Departments of Surgery and Internal Medicine, Omiya Medical Center, Jichi Medical School, Omiya, Saitama 330, Japan ABSTRACT The effect of tamoxifen, an antiestrogenic agent, on lipid metabolism was studied in postmenopausal patients with breast cancer who received the drug for postoperative adjuvant treatment following mastectomy. To measure total cholesterol and triglyceride concentrations, fasting blood samples were collected before and 2 months after the initiation of tamoxifen therapy from 16 patients who satisfied the study criteria. All patients were normolipidemic before tamoxifen was administered. Control samples were obtained from hypertriglyceridemia patients who were free from breast cancer. Marked hypertriglyceridemia was observed in 3 of 16 patients after tamoxifen treatment. The activity of lipoprotein lipase and hepatic
T
AMOXIFEN (TAM), a nonsteroidal estrogen antagonist, has been widely used since the 1970s in adjuvant hormonal treatment of primary breast cancer (1). TAM interferes with the estrogen-dependent proliferation of breast cancer cells and improves the postoperative prognosis of patients with breast cancer of postmenopausal onset (2, 3). Although the optimal duration of adjuvant treatment has not yet been determined, the currently available limited data suggest that the longer the treatment, the more beneficial, and that administration of TAM for 5 yr significantly reduces the recurrence of carcinoma (4 –7). The side effects of TAM are generally mild, including those affecting lipoprotein metabolism. Although several studies described small changes in plasma lipoprotein concentrations, most of the changes reduce the risk of cardiovascular disease (8 –14). However, a case of marked TAM-induced hypertriglyceridemia also was reported by Brun et al. (15). We recently found a severely elevated triglyceride (TG) level exceeding 2000 mg/dL, which may induce lethal pancreatitis in these patient (Hozumi Y., M. Kawano, T. Saito, M. Miyata; unpublished data). This patient was not included in this study. Therefore, the effects of TAM on lipid metabolism should not be ignored. To study the mechanisms of TAM-induced hyperlipidemia, we prospectively studied the lipolytic enzymes in postheparin plasma (PHP) before and 8 weeks after TAM administration; TAM has been shown to require approximately 4 weeks to reach steady state (16). We also tested the susceptibility of serum TG from patients treated with TAM to the hydrolytic activity of purified lipoprotein lipase (LPL). Received May 3, 1997. Revision received November 20, 1997. Accepted January 14, 1998. Address all correspondence and requests for reprints to: Dr. Hozumi Departments of Surgery and Internal Medicine, Omiya Medical Center, Jichi Medical School, 1– 847 Amanuma-cho, Omiya, Saitama 330, Japan. E-mail:
[email protected].
triglyceride lipase, the key enzymes of triglyceride metabolism, decreased significantly in all of 16 patients as a result of tamoxifen treatment (P 5 0.008 and P 5 0.007, respectively). However, the mean mass of lipoprotein lipase significantly increased (P 5 0.011) after tamoxifen treatment. We therefore conclude that tamoxifen might increase inactive lipoprotein lipase. Because marked hyperlipidemia is a potent risk factor for life-threatening acute pancreatitis and arteriosclerosis, plasma lipid levels should be tested periodically during tamoxifen treatment, even if the patients are normolipidemic during the pretreatment stage. (J Clin Endocrinol Metab 83: 1633– 1635, 1998)
Materials and Methods Sixteen postmenopausal women with resectable breast cancer were recruited consecutively at Omiya Medical Center, Jichi Medical School, and one of its affiliated hospitals. Informed consent was obtained from all patients, and the project was carried out according to the Declaration of Helsinki. All patients satisfied the following criteria: all were over 50 yr of age; none had received radiation or chemotherapy before breast surgery; all underwent a total mastectomy with axillary dissection for potentially curable, histopathologically confirmed, axillary node-negative breast cancer; none had diabetes mellitus or renal or hepatic diseases; and none had received drugs known to affect lipid and lipoprotein levels. All patients were instructed to follow their usual diets during the study period. Overnight fasting blood samples were collected under identical conditions from the study patients before and 2 months after they began TAM therapy to measure their total cholesterol (TC) and TG levels. At the same time the fasting blood samples were collected, samples to determine the mass and the activity of lipoprotein lipase and activity of hepatic triglyceride lipase (HTGL) in PHP were obtained from all patients 10 mins after iv injection of heparin (50 U/kg body weight). The samples were immediately frozen and stored at 220 C until the mass and the activity of LPL and activity of HTGL were assayed. TC and TG levels were measured by an enzymatic method. LPL mass was measured using enzyme immunoassay (EIA) of Ikeda’s method (17). The LPL and HTGL activities were determined using a modified method of Belfrage and Vaughan (18). The susceptibility of serum TG from patients treated with TAM (n 5 16) to hydrolysis by LPL was analyzed. Control sera from age-matched breast cancer-free female patients with hypertriglyceridemia were obtained from the lipid clinic of our medical center. Four hundred and fifty microliters of serum added to 50 mL purified LPL (1350 units/mL, Sigma Co., St. Louis, MO) was incubated at 37 C for 30 min, and the remaining TG then was measured.
Statistical analysis Results were expressed as mean 6 se. For comparison, Student’s t tests for paired and unpaired data were used.
Results
Figure 1 shows the serum TC and TG levels before and after TAM treatment. The mean TG levels increased signif-
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FIG. 1. TC and TG concentrations before and after treatment with TAM. N.S., Not significant. (No. patients 5 16).
icantly after TAM administration (P 5 0.0026) from 134 mg/dL to 182 mg/dL; the mean TC levels remained unchanged. After 12 months, both levels were similar to those at the 2-month point (data not shown). Figure 2 shows the activity and mass of LPL in PHP before and after TAM treatment. The mean LPL concentration decreased significantly (P 5 0.0081) from 0.409 mmol/mL per min to 0.337 mmol/mL per min. However, the mean mass significantly increased (P 5 0.0112) after TAM treatment from 207 ng/mL to 271 ng/mL. The activity of HTGL following TAM treatment decreased significantly (P 5 0.0067) from 0.252 mmol/mL per min to 0.202 mmol/mL per min (Fig. 3). Figure 4 shows the effect of purified LPL treatment on the concentrations of TG in serum from the patients with breast cancer and control patients. There were no significant differences in the susceptibility to LPL between the sera from the patients with breast cancer and the control patients. Discussion
FIG. 2. LPL mass and activity before and after treatment with TAM. (No. patients 5 16).
FIG. 3. HTGL before and after treatment with TAM. (No. patients 5 16).
FIG. 4. Serum TG Levels after treatment with purified LPL. (No. patients and controls 5 16).
In 1995, the consensus conference recommended the use of TAM in all patients with breast cancer of postmenopausal onset (19). TAM also has been used prophylactically in normal women to prevent breast cancer (1). Thus, the drug is currently prescribed to millions of women worldwide for the adjuvant therapy or prevention of breast cancer. The trend toward long-term administration of TAM necessitates careful observation of the side effects of the drug. Generally, TAM is believed not to induce any serious adverse effects even after extended periods of administration. However, derangement imbalances in serum lipoprotein metabolism, i.e. decreases in the concentration of total and low-density lipoprotein cholesterol and increases in the concentration of TGs and high-density lipoprotein cholesterol, have been reported previously (8, 11, 12, 20). We studied one case of marked hypertriglyceridemia induced by TAM (Hozumi, Y., M. Kawano, T. Saito, M. Miyata; unpublished data). Brun et al. (15) also reported another such case, in which impaired clearance of circulating TG resulted in the decreased activity of both LPL and HTGL. However, the mechanisms underlying these changes in serum lipids and lipoproteins are not well understood. In the present study, we confirmed the observations of Brun et al., (15), i.e. decreased activities of the two lipolytic
EFFECT OF TAM ON SERUM LIPID METABOLISM
enzymes, not only in the patients with hyperlipidemia but also in those who remained normolipidemic. Interestingly, the LPL concentration increased despite its decreased activity; the reason for this is unclear. However, an increase of inactive LPL protein in some hyperlipidemic patients was previously reported (21). For some unknown reason, some patients did not have a significant increase of serum TG even after their LPL and HTGL activity decreased. The susceptibility of serum lipoproteins from patients who received TAM treatment to the hydrolytic activity of LPL was not altered when it was examined using purified LPL. We hypothesized that: 1) TAM reduces LPL and HTGL activity, resulting in an increase of serum TG and very low density lipoprotein (VLDL) cholesterol; 2) TAM may increase the concentration of inactive LPL; and 3) plasma VLDL from patients treated with TAM normally reacts to purified LPL. Estrogen induces hyperlipidemia through its multiple effects on lipid metabolism, including increased synthesis of TG and VLDL and decreased activity of LPL and HTGL (22). TAM is essentially antiestrogenic, but it has some estrogenic activities. The effects of TAM on lipid metabolism may be attributable to its complex combination of estrogenic and antiestrogenic activities, although other mechanisms cannot be excluded. Acknowledgment We are indebted to Prof. Masanobu Kawakami of Omiya Medical Center, Jichi Medical School, for discussion and help in the preparation of the manuscript.
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