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Technical Briefs |
1
Department of Laboratory Medicine, National Taiwan University Hospital, and
2
Department of Laboratory Medicine, Taipei City Psychiatric Center, Taipei 100, Taiwan, Republic of China
aaddress correspondence to this author at: Department of Laboratory Medicine, College of Medicine, and National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan; fax 886-2-2322-4263, e-mail kstsaimd{at}ha.mc.ntu.edu.tw
Estrogen (1)(2)(3)(4)(5) may increase hepatic production of thyroxine-binding globulin (TBG) and decrease TBG clearance (6), thus increasing serum total thyroxine (tT4) (3)(4) and, to a lesser extent, total triiodothyronine (tT3) (3)(4). As a result, increased tT4 and tT3 are seen in states of excessive estrogen and/or progestin, such as pregnancy, estrogen replacement therapy (HRT) (5), and oral contraceptive usage (1). This phenomenon may cause problems in clinical diagnoses when tT4 or tT3 is used for these patients. On the other hand, estrogen has been shown to increase thyroid-stimulating hormone (TSH) and to decrease free thyroxine (fT4) through a mild inhibitory effect on the thyroid gland (4). Compound that are analogs of estrogens, such as tamoxifen, have been shown to increase TSH without decreasing fT4 (7)(8). Recently, a new category of therapeutic agents, collectively termed selective estrogen receptor modulators (SERMs), has been developed to treat patients with postmenopausal osteoporosis (9). Raloxifene is one SERM. It decreases bone resorption (9)(10) and serum LDL-cholesterol (9)(11)(12), but it does not stimulate breast (13) or endometrium (14) at the recommended dosage of 60 mg daily. This agent is becoming one of the first-line pharmaceutical agents for postmenopausal osteoporosis and is currently administered to a large number of patients. However, the effect of long-term raloxifene usage on TBG, T3 uptake, tT3, tT4, fT4, and TSH has not been well documented. To investigate whether raloxifene causes changes in serum concentrations of these markers, we compared the effects of 1 year of treatment with either raloxifene or combined continuous estrogen and progesterone (CCEP) on the thyroid function test profiles, estradiol 2 (E2), and follicle-stimulating hormone (FSH).
We studied 60 euthyroid postmenopausal women (age range, 40–75 years) with relatively low bone mineral density. The t-score, using the mean and SD of healthy premenopausal Taiwanese women as reference (15), ranged from +1 to -2.49. These 60 women were divided into two groups in a double-blind, randomized fashion. Fifty women received raloxifene (60 mg daily) before breakfast, and 10 women received combined conjugated equine estrogen (premarin®; 0.625 mg) and medroxyprogesterone acetate (provera®; 5 mg) daily. Fasting serum samples were collected for all participants at baseline and after 1 year of treatment. All of the serum samples were stored at -70 °C, thawed simultaneously, and measured on the same day. All participants completed the treatment program. The compliance was good for both groups. Pill counting showed that each patient consumed 85–100% of the tablets/capsules.
Serum tT3, tT4, fT4, TBG, third-generation TSH, T3 uptake, E2, and FSH were all measured using commercial chemiluminescent immunoassays and instruments (Immulite; DPC). The within-day imprecision (CVs) of these assays was 3–7%.
We used two-way ANOVA for repeated measures to compare the concentrations of E2 and FSH and the thyroid function profiles between the two therapeutic groups, before and after treatment. The data were analyzed by the general linear model procedure (PROG GLM) included in the SAS package (SAS, Ver. 6.12; SAS Institute).
The anthropometric data and the mean value (± SE) for each thyroid
function test item before and after treatment in the CCEP and
raloxifene groups are shown in Table 1
. At baseline, there was no significant difference in height,
weight, age, years since menopause, or thyroid function test items
between these two groups. CCEP significantly increased serum TBG
(17%), tT3 (5.7%), and
tT4 (19%) and decreased T3
uptake (9%), whereas it did not change TSH. The mean
fT4 concentration decreased by 3%, but the
change was not statistically significant. Raloxifene also increased
serum TBG (7.8%), tT3 (4.4%), and
tT4 (5.7%) and decreased
T3 uptake (3.7%). The mean
fT4 concentration decreased by 3%, but this
change was not statistically significant (Table 1
). The changes in
these five markers were apparently smaller than those caused by CCEP
but did not reach statistical significance.
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Raloxifene did not change serum concentrations of HDL-cholesterol (12) or C-reactive protein (16). On the contrary, CCEP increases the serum concentrations of C-reactive protein (16) and HDL-cholesterol (12). Thus, SERMs such as raloxifene may have different effects on certain serum proteins compared with estrogen. In this study, we showed that the usual dosage of raloxifene administered for 1 year increased serum TBG. This increase in TBG is similar to the effects of CCEP and may then be associated with an increase of tT4 and tT3, whereas TSH and fT4 were not significantly changed. The slight but insignificant decreases in fT4 in both groups after 1 year of treatment were compatible with the findings that showed a mild suppression of thyroid function by tamoxifen (7) and estrogen (4). Our findings indicated that in patients treated with raloxifene, the results of tT3 and tT4 tests should be interpreted with caution because they could be falsely increased.
References
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