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Cited by 267Thyroid Disorders and TreatmentsMenopause: Health Impacts and TreatmentsEstrogen and related hormone effects

Increased need for thyroxine in women with hypothyroidism during estrogen therapy

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Arafah, Baha M.·2001·New England Journal of Medicine
DOI 10.1056/nejm200106073442302
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Abstract

BACKGROUND: Women with hypothyroidism that is being treated with thyroxine often need higher doses when they are pregnant. Whether this need can be attributed solely to estrogen-induced increases in serum thyroxine-binding globulin or whether other factors are involved is not known. METHODS: In 11 postmenopausal women with normal thyroid function and 25 postmenopausal women with hypothyroidism treated with thyroxine, I assessed thyroid function before they started estrogen therapy and every 6 weeks for 48 weeks thereafter. The women with hypothyroidism included 18 women receiving thyroxine-replacement therapy and 7 women receiving thyrotropin-suppressive thyroxine therapy. On each occasion, serum thyroxine, free thyroxine, thyrotropin, and thyroxine-binding globulin were measured. RESULTS: In the women with normal thyroid function, the serum free thyroxine and thyrotropin concentrations did not change, whereas at 12 weeks the mean (+/-SD) serum thyroxine concentration had increased from 8.0+/-0.9 microg per deciliter (103+/-12 nmol per liter) to 10.4+/-1.5 microg per deciliter (134+/-19 nmol per liter, P<0.001) and the serum thyroxine-binding globulin concentration had increased from 20.3+/-3.5 mg per liter to 31.3+/-3.2 mg per liter, P<0.001). The women with hypothyroidism had similar increases in serum thyroxine and thyroxine-binding globulin concentrations during estrogen therapy, but their serum free thyroxine concentration decreased from 1.7+/-0.4 ng per deciliter (22+/-5 pmol per liter) to 1.4+/-0.3 ng per deciliter (18+/-4 pmol per liter, P<0.001) and their serum thyrotropin concentration increased from 0.9+/-1.1 to 3.2+/-3.1 microU per milliliter (P<0.001). The serum thyrotropin concentrations increased to more than 7 microU per milliliter in 7 of the 18 women in the thyroxine-replacement group and to more than 1 microU per milliliter in 3 of the 7 women in the thyrotropin-suppression group. CONCLUSIONS: In women with hypothyroidism treated with thyroxine, estrogen therapy may increase the need for thyroxine.

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  • Estrogen, tamoxifen, raloxifene, clofibrate, opioids, mitotane, fluorouracil, and capecitabine increase serum TBG.

    “Examples of drugs that increase serum TBG from insignificant to significant degrees, include estrogen (201), tamoxifen (202), raloxifene (203), clofibrate (204), opioids (205), mitotane (206), fluorouracil (207), and capecitabine (208).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [201]

  • Estrogen therapy in postmenopausal women increased mean TSH from 0.9 to approximately 3.2 mIU/L 12 weeks after initiation.

    “With respect to the classic case of estrogen treatment in postmenopausal women, such therapy was associated with an increase in mean TSH concentration from 0.9mIU/L to approximately 3.2 mIU/L 12 weeks after initiation of estrogen therapy in a prospective nonrandomized study (201).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [201]

  • Conditions increasing the serum TBG concentration (eg, elevated estrogen levels) or enhancing the renal clearance of serum proteins (eg, nephrotic syndrome) can reduce the bioavailability of LT4.

    “Conditions increasing the serum TBG concentration (eg, elevated estrogen levels) or enhancing the renal clearance of serum proteins (eg, nephrotic syndrome) can reduce the bioavailability of LT4 (34–36).”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [34]

  • Estrogen can increase TBG and albumin concentrations and decrease FT4 levels, whereas androgen has the opposite effects.

    “Estrogen can increase TBG and albumin concentrations and decrease FT4 levels, whereas androgen has the opposite effects (34, 91).”

    From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [34]

  • In postmenopausal women taking LT4, initiation of oestrogen therapy was associated with increases in serum TBG, TT4, and TSH, and a decrease in serum FT4 concentration.

    “In postmenopausal women taking LT4, the initiation of oestrogen therapy was associated with increases in serum TBG, TT4 and TSH, and a decrease in the serum FT4 concentration [ 89 ].”

    From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [89]

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Authors
Arafah, B. M.
Affiliations
University Hospitals of Cleveland (US)
Corresponding author
Arafah, Baha M.
ORCID
Arafah, Baha M.
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2001-06-07
Volume
344
Issue
23
Pages
1743-1749
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm200106073442302
OpenAlex
W2314885285
Cited by
267
References
13
Citations by year
2026: 4 · 2025: 9 · 2024: 6 · 2023: 12 · 2022: 9 · 2021: 22 · 2020: 5 · 2019: 13 · 2018: 9 · 2017: 4 · 2016: 5 · 2015: 13 · 2014: 12 · 2013: 10 · 2012: 10
FWCI
10.34
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
hypothyroidism, estrogen therapy, thyroxine-binding globulin, free thyroxine, thyroid-stimulating hormone, postmenopausal women, thyroxine replacement, thyroid function monitoring, hormone replacement therapy, thyroid autoimmunity, thyroid cancer risk
MeSH terms
Adult, Estrogens, Conjugated (USP), Female, Humans, Hypothyroidism, Medroxyprogesterone, Middle Aged, Reference Values, Thyroid Function Tests, Thyroid Gland, Thyroid Neoplasms, Thyrotropin, Thyroxine, Thyroxine-Binding Proteins, Postmenopause, Hormone Replacement Therapy

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