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Thyroid Division (E.M., L.E.B.) and Endocrine and Hypertension Division (J.E.L., J.S.C., E.W.S.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115
Address correspondence to: Ellen Marqusee, M.D., Thyroid Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115. E-mail: emarqusee{at}bics.bwh.harvard.edu
Abstract
Estrogen is known to increase serum T4-binding globulin (TBG) concentrations, thereby increasing serum total T4 concentrations. Serum free T4 concentrations, however, remain normal. Tamoxifen, a selective estrogen receptor modifier (SERM), also raises serum TBG concentrations, but whether newer SERMs with less stimulatory action on the endometrium do so is not known. We, therefore, compared the effect of droloxifene, a SERM, and conjugated equine estrogen on pituitary-thyroid function in normal postmenopausal women.
Ten women were treated for 6 weeks with conjugated estrogen (Premarin), 0.625 mg/day, and droloxifene, 60 mg/day, in a double-blind crossover study with an intervening 4-week no-treatment period. We measured serum T4, T3, TBG, free T4 index, and TSH at baseline and at the end of each 6-week period. The baseline values were compared with the 6-week values using paired t tests.
The mean (±SD) serum TBG concentrations increased significantly during both treatment periods (baseline, 1.5 ± 0.4 mg/dL; conjugated estrogens, 2.7 ± 0.6 mg/dL; droloxifene, 2.1 ± 0.6 mg/dL; P < 0.001 and P = 0.001, respectively). There were no significant changes in the serum free T4 index. Serum T4 and T3 concentrations increased during both treatment periods, however, the increase was significant only for T4 during the conjugated estrogen treatment period. The serum TSH concentrations increased significantly during both treatment periods (18% during conjugated estrogen and 11% during droloxifene), and the values remained within the normal range in all women.
Administration of both conjugated estrogen and droloxifene for 6 weeks increases serum TSH and TBG concentrations, but does not alter free T4 index values in postmenopausal women.
ESTROGEN IS KNOWN to increase serum T4-binding globulin (TBG) concentrations due to decreased clearance of more heavily sialylated TBG secreted by the liver (1). As a result, serum total T4 concentrations increase whereas serum free T4 concentrations remain normal. In hypothyroid women treated with T4 who become pregnant, serum TSH concentrations often increase, and, on average, the dose of T4 has to be raised by 45% (2, 3). Whether the increased requirement for T4 is due only to the increase in serum TBG concentrations that occurs in pregnant women is not certain but raises the question of whether estrogen therapy may also increase the requirements for T4 in postmenopausal women.
Tamoxifen, a selective estrogen receptor modifier (SERM) used predominantly for the treatment and prevention of breast cancer, has been reported to increase serum TBG concentrations (4, 5). Unlike tamoxifen, newer SERMs that are currently available or in development for prevention or treatment of osteoporosis (such as raloxifene or droloxifene) have estrogen antagonist properties in the uterus. There have been no reported studies evaluating the effect of these newer SERMs on serum TBG concentrations or thyroid function in euthyroid women. We, therefore, studied pituitary-thyroid function in normal postmenopausal women treated with both conjugated estrogen and droloxifene, a SERM structurally similar to tamoxifen (6).
Subjects and Methods
Study subjects
We studied 10 normal postmenopausal women. None had a history of thyroid disease or were taking thyroid hormone, and none had taken estrogen for at least 3 months before the study. The study was approved by the Brigham and Women’s Hospital Human Subjects Committee, and all the women gave informed consent.
Study design
The women were studied at baseline and after 6 weeks of treatment with conjugated estrogen (Premarin), 0.625 mg/day, and droloxifene, 60 mg/day, given in a random order with an intervening no-treatment period of 4 weeks. The study, which was double blinded, was initially designed to compare the effects of the two treatments on lipoprotein metabolism. Blood samples were drawn at baseline, at the end of each 6-week treatment period, and at the end of the no-treatment period. All blood samples were drawn at the same time in the morning. The serum samples were frozen and analyzed for T4, T3, thyroid hormone-binding ratio (THBR), TBG, and TSH after completion of the study.
Hormone analysis
Serum TSH, T4, and T3 were measured using chemiluminescent immunoassays (Beckman, New York, NY). The intra-assay coefficients of variation for these assays were 3.3, 4.9, and 4.5%, respectively. THBR was measured using a solid phase 125I radioassay T3-uptake test (Diagnostics Products Corporation, Los Angeles, CA) normalized to that of a reference serum value. The intra-assay coefficient of variation for THBR was 4.3%. The serum free T4 index was calculated as the product of the serum T4 and THBR values. Serum TBG was measured using a chemiluminescent immunoassay (Diagnostics Products, Cirrus, NJ) with an intra-assay coefficient of variation of 7.1%. Serum thyroid peroxidase antibodies (TPO Abs) were measured using an enzyme immunometric assay (ALPCO, Windham, NH). All samples from an individual woman were analyzed in the same assay.
Statistical analysis
Because the effect of estrogen to increase serum TBG concentrations may last more than 6 weeks (7), the baseline values instead of those at the end of the no-treatment period were compared with each posttreatment value using two-tailed paired t tests. An analysis for differential carryover effect was used to test for an order effect. In a secondary analysis, baseline values were also compared with values at the end of the no-treatment period using two-tailed paired t tests.
Results
The mean (±SD) age of the 10 women was 58 ± 5 yr (range, 50–66). All women were 3 yr or more postmenopausal. Only one woman had positive TPO Abs (191 IU/mL).
Serum TBG concentrations increased from 1.5 ± 0.4 to 2.7 ±
0.6 mg/dL during treatment with conjugated estrogen (P
< 0.001) and to 2.1 ± 0.6 mg/dL during treatment with
droloxifene (P = 0.001). The magnitude of the increase
in serum TBG was significantly greater with conjugated estrogens as
compared with droloxifene (P < 0.001). Serum total
T4 and T3 concentrations increased during both
treatment periods, but only during the conjugated estrogen period was
the increase statistically significant (Table 1
).
|
). No women had a supernormal serum TSH concentration at
any time. The increase in serum TSH was slightly greater during
conjugated estrogen treatment than droloxifene treatment (Table 1).
However, the magnitude of the increase was not significantly different
between the two medications. Nine of the 10 women had an increase in
serum TSH concentration after 6 weeks of conjugated estrogen treatment,
and eight women had an increase after droloxifene (Fig. 1).
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Discussion
Conjugated estrogen, at the 0.625 mg/day dose most typically prescribed for postmenopausal women, and droloxifene, both given for 6 weeks, increased serum TSH concentrations within the normal range in normal women. In addition, although the serum total T4 and T3 concentrations increased due to the increase in serum TBG concentrations, serum free T4 index values did not change. The increase in serum TBG concentration with conjugated estrogen was twice that observed with droloxifene.
The increase in serum TBG concentrations during conjugated estrogen treatment is consistent with previous reports. Chetkowski et al. (8) reported a similar increase in serum TBG concentrations after conjugated estrogen treatment with 0.625 mg/day for 4 weeks. Others (7, 9) have reported slightly smaller changes after 6 weeks of conjugated estrogen at the same dose. In a prior study, the effect of conjugated estrogen on serum TBG concentrations lasted longer than 6 weeks (7), whereas the concentrations returned to baseline after 4 weeks in our study.
In prior studies of women treated with conjugated estrogen in doses ranging from 0.625–2.5 mg/day, there was no change in serum TSH concentrations (7, 9, 10, 11). In a recent abstract, however, 4 of 52 perimenopausal and postmenopausal women had "elevated" serum TSH concentrations after 1 month of estrogen therapy (12). In the present study, serum TSH concentrations increased significantly within the normal range after 6 weeks of conjugated estrogen treatment. The difference in these findings may be due to the timing of the measurements, the study design (parallel vs. crossover) or the assays used (10, 11).
Little is known about the effect of SERMs on thyroid function in postmenopausal women. Serum TBG concentrations in postmenopausal women given tamoxifen for at least 6 months increased 24% (13). In the present study, serum TBG increased 41% after 6 weeks of droloxifene administration, suggesting that, although structurally similar to tamoxifen, droloxifene may have a more pronounced effect on serum TBG. Whether this is due to greater estrogen agonist properties on the liver or is dose related is unclear.
The effect of tamoxifen on TSH secretion is controversial. In two studies, serum TSH concentrations did not increase in euthyroid women given tamoxifen (20 mg daily) for up to 3 months (4, 5). However, in another study there was an increase in serum TSH concentrations and a decrease in serum free T4 concentrations in women treated with 30 mg tamoxifen daily for 13 months (13). We are aware of no published studies evaluating thyroid function in women taking SERMs other than tamoxifen.
The increase in serum TSH concentrations with both conjugated estrogen and droloxifene is probably due to a decrease in serum free T4 concentrations caused by the increase in serum TBG concentrations. The increase in serum TSH would be expected to increase T4 secretion and return the serum free T4 concentrations to the baseline value. The exact timing of this sequence of events and when serum T4 and TSH concentrations return to baseline is not known. Both timing of our blood samples and the possibility of assay sensitivity for free T4 index may explain why we did not detect a decrease in the free T4 index at 6 weeks, despite the increase in serum TSH. In addition, it is possible that the serum TSH would have returned to baseline had we continued our study for longer than 6 weeks.
The results of our study suggest that both conjugated estrogen and droloxifene, a new SERM, affect thyroid function in euthyroid women. Whereas normal women remain euthyroid when given conjugated estrogen and droloxifene for 6 weeks, hypothyroid women may not be able to respond to the increase in serum TBG concentration by increasing endogenous T4 and T3 secretion. Therefore, hypothyroid women taking T4 might need a larger dose when treated with estrogen, as recently reported in abstract form (9), or a SERM similar to what occurs when T4-treated hypothyroid women become pregnant. It would seem advisable, therefore, to measure serum TSH in hypothyroid T4-treated women, women with subclinical hypothyroidism, or women with positive TPO Abs 2–3 months after initiation of conjugated estrogen or SERM therapy.
Footnotes
1 Supported by a grant from Pfizer Pharmaceuticals (to E.W.S.),
Harvard Medical School Scholar in Medicine Fellowship (to E.W.S.),
Thyroid Center of Excellence grant from Knoll Pharmaceuticals, and NIH
Grants DK18919 (to L.E.B.) and GCRC M01-RR-02635. 
2 Present address: Section of Endocrinology, Diabetes and Nutrition,
Boston Medical Center, Boston University School of Medicine, Boston,
Massachusetts 02118.
Received March 29, 2000.
Revised July 11, 2000.
Accepted August 4, 2000.
References
This article has been cited by other articles:
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  A. P. Heaney, V. Nelson, M. Fernando, and G. Horwitz Transforming Events in Thyroid Tumorigenesis and Their Association with Follicular Lesions J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 5025 - 5032. [Abstract] [Full Text] [PDF]
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