The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1633-1635
Copyright © 1998 by The Endocrine Society
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
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: yahozumi{at}omiya.jichi.ac.jp
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Abstract
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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 triglyceride lipase, the key enzymes of
triglyceride metabolism, decreased significantly in all of 16 patients
as a result of tamoxifen treatment (P = 0.008 and
P = 0.007, respectively). However, the mean mass of
lipoprotein lipase significantly increased (P =
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.
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Introduction
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TAMOXIFEN (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, 5, 6, 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, 9, 10, 11, 12, 13, 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).
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Materials and Methods
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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 -20 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 =
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 µL 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 ± SE. For
comparison, Student’s t tests for paired and unpaired data
were used.
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Results
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Figure 1
shows the serum TC and TG
levels before and after TAM treatment. The mean TG levels increased
significantly after TAM administration (P = 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 =
0.0081) from 0.409 µmol/mL per min to 0.337 µmol/mL per min.
However, the mean mass significantly increased (P =
0.0112) after TAM treatment from 207 ng/mL to 271 ng/mL. The activity
of HTGL following TAM treatment decreased significantly
(P = 0.0067) from 0.252 µmol/mL per min to 0.202
µmol/mL per min (Fig. 3).
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Figure 1. TC and TG concentrations before and after
treatment with TAM. N.S., Not significant. (No. patients =
16).
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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.
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Discussion
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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 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.
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Acknowledgments
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We are indebted to Prof. Masanobu Kawakami of Omiya Medical
Center, Jichi Medical School, for discussion and help in the
preparation of the manuscript.
Received May 3, 1997.
Revised November 20, 1997.
Accepted January 14, 1998.
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Abstract
Introduction
