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Cited by 57Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryHistorical Medical Research and Treatments

Thyroxine and treatment of hypothyroidism: seven decades of experience

Open access
Mateo, Roselyn Cristelle I., Hennessey, James V.·2019·Endocrine
DOI 10.1007/s12020-019-02006-8PMC PMC6794242
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Abstract

Hypothyroidism is one of the most common endocrine disorders, affecting as much as 10% of the global population. There is a rich cultural milieu of treatment history and interventions dating as far back as 2 millennia. Chinese cretins were treated with sheep thyroid in the 6th century. In 1890, transplanted animal thyroid tissue resulted in a prompt clinical response in a myxedematous patient, and in 1891 injections of sheep thyroid were reported. One year later, the oral administration of fresh sheep thyroid glands was noted to be effective. Within a few years, the danger of over-dosage with extracts was recognized and dosing guidance indicated a low dose start and gradual increase as required based on symptoms. Orally ingested extracts became widespread and by 1914 thyroxine had been crystallized. In 1927, thyroxine, was synthesized as an acid, limiting oral absorption. Finally a sodium salt of thyroxine was introduced in 1949. These synthetic preparations were then made available for clinical use. Prior to 1970, extracts and combination therapy with synthetic LT4 and LT3 were standard replacement until the peripheral deiodinase-mediated T4 to T3 conversion documented the endogenous generation of T3 from LT4 in athyreotic subjects. This resulted in advocacy for patients previously treated with combinations and desiccated thyroid be transitioned to L-thyroxine monotherapy. The determination of the optimal dose has evolved such that now a general recommendation for replacement dosage of LT4 is 1.6-1.7 mcg/kg/day. Thyroid hormone extracts were established prior to the FDA's establishment in 1906, and when the Food, Drug, and Cosmetic act of 1938 enhanced the FDA's regulatory authority. In 1997, FDA declared LT4 products to be new drugs subject to regulation and quickly a pharmacokinetic process to determine interchangeability among approved LT4 products ensued. Differences in bioavailability of 12.5% or more may be considered therapeutically equivalent and therefore such products interchangeable. To assure refill to refill consistency, all levothyroxine sodium products now meet a 95-105% potency specification throughout their labeled shelf-lives. Seventy years after Kendall's great achievement in isolating thyroxine, we have thyroxine products with precise amounts of synthetic hormone that meet demanding regulations to assure high product quality, predictable bioavailability given its narrow therapeutic range, and now are left with potential variance in the therapeutic efficacy among different preparations.

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  • Levothyroxine sodium shows markedly increased solubility and more reliable intestinal absorption compared to free acid form of T4, and is now the API of T4 tablets.

    “Levothyroxine sodium shows a markedly increased solubility and more reliable intestinal absorption compared to the free acid form of T4, and it is now the active pharmaceutical ingredient (API) of T4 tablets (17).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [17]

    The “Discoveries in the 20th century” section says the acid form limited oral absorption and that a sodium salt was introduced in 1949. The “FDA regulations” section discusses current levothyroxine sodium products and LT4 tablets. Our copy does not state that the sodium salt has markedly greater solubility or more reliable intestinal absorption than the acid form. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The dose of LT4 required to maintain a euthyroid state is one that alleviates symptoms of hypothyroidism and maintains serum TSH level within reference interval.

    “The dose of LT4 required to maintain a euthyroid state is one that alleviates symptoms of hypothyroidism and maintains serum TSH level within the reference interval (17).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [17]

    The paper’s “Radioimmunoassay-based thyroid function tests” section (page unavailable) says LT4 treatment was titrated to normalize TSH. But “Response of peripheral markers of hypothyroidism with l-thyroxine monotherapy” (page unavailable) reports that some patients retained hypothyroid symptoms despite normal TSH, so the source does not establish symptom relief as a necessary feature of a dose that maintains biochemical euthyroidism. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • LT4 is a safe, effective hormone replacement therapy for hypothyroidism caused by autoimmune thyroiditis, partial or total thyroidectomy, radioiodine treatment, or drug side effects.

    “The drug levothyroxine (LT4) constitutes a safe, effective hormone replacement therapy for hypothyroidism caused by autoimmune thyroiditis, partial or total thyroidectomy, radioiodine treatment, or drug side effects [ 1 – 5 ].”

    From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [3]

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Authors
Mateo, R. C. I., & Hennessey, J. V.
Affiliations
  • Rush University Medical Center (US)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Mateo, Roselyn Cristelle I.
ORCID
Hennessey, James V.
Venue
Endocrine
Publisher
Springer Science and Business Media LLC
Published
2019-07-18
Volume
66
Issue
1
Pages
10-17
ISSN
  • 0969-711X (ISSN-L)
  • 1355-008X
  • 1559-0100
DOI
10.1007/s12020-019-02006-8
PMC
PMC6794242
OpenAlex
W2960733516
Cited by
57
References
87
Citations by year
2026: 4 · 2025: 12 · 2024: 12 · 2023: 4 · 2022: 10 · 2021: 13 · 2020: 2
FWCI
0.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Historical Medical Research and Treatments
Keywords
hypothyroidism, levothyroxine, thyroid hormone replacement, thyroid extract, desiccated thyroid, T4 to T3 conversion, bioavailability, therapeutic window, dose optimization, myxedema
MeSH terms
Endocrinology, Humans, Hypothyroidism, Thyroid Function Tests, Thyroxine, United States, United States Food and Drug Administration, History, 19th Century, History, 20th Century, History, 21st Century

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