Evaluation of the Adequacy of Levothyroxine Replacement Therapy in Patients with Central Hypothyroidism1
Abstract
As there are few data on the evaluation of the adequacy of levothyroxine (l-T4) therapy in patients with central hypothyroidism (CH), a prospective study was performed to assess the accuracy of various parameters in the follow-up of 37 CH patients. Total and free thyroid hormones, TSH, and a series of clinical and biochemical indexes of peripheral thyroid hormone action have been evaluated off and on l-T4 therapy. Samples were taken before the daily administration of l-T4. In all patients off therapy, clinical hypothyroidism and low levels of free T4 (FT4) were observed, whereas values of FT3, total T4, and total T3 were below the normal range in 73%, 57%, and 19% of cases, respectively. Most of the indexes of thyroid hormone action were significantly modified after l-T4 withdrawal and exhibited significant correlation with free thyroid hormone levels. During l-T4 replacement therapy, 32 patients had circulating levels of FT4 and FT3 and indexes within the normal range with a mean l-T4 daily dose of 1.5 ± 0.3 μg/kg BW. Despite normal serum FT4, 3 patients had borderline high values of FT3 and a clear elevation of serum-soluble interleukin-2 receptor concentrations, suggesting overtreatment. Low or borderline low FT4/FT3 levels indicated undertreatment in 2 patients. The clinical parameters lack the required specificity for the diagnosis or follow-up of CH patients. The l-T4 daily dose should be established, taking into account the weight, the age, and the presence of other hormone deficiencies or pharmacological treatment of CH patients. In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring TSH and FT4 concentrations. In the evaluation of the adequacy of l-T4 replacement therapy, both FT4 and FT3 serum levels together with some biochemical indexes of thyroid hormone action are all necessary to a more accurate disclosure of over- or undertreated patients.
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Manifestations of central hypothyroidism are similar to those of primary hypothyroidism, but they can be masked by coexistent multiple pituitary hormone deficiency.
“Manifestations of CeH are similar to those of primary hypothyroidism, but they can be masked by coexistent MPHD [1, 24, 25].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [24]
Younger CeH patients require higher L-T4 doses than older CeH patients.
“As in primary hypothyroidism [53], younger CeH patients require higher doses than the older ones [24, 25].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [24]
Overt central hypothyroidism is most frequently indicated by the combined findings of low FT4 with low or normal TSH concentrations.
“Overt CeH is most frequently indicated by the combined findings of low FT4 with low or normal TSH concentrations [24, 25].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [24]
Mean L-T4 daily doses of 1.2-1.6 μg/kg bw/day were judged sufficient in the large majority of adult CeH patients.
“Indeed, mean L-T4 daily doses of 1.2-1.6 μg/kg bw/day were judged sufficient in the large majority of adult CeH patients, with the main aim of achieving a more appropriate metabolic profile [24, 25, 55].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [24]
In CeH patients, serum TSH concentrations are rapidly suppressed in a large portion during L-T4 administration.
“In particular, serum TSH concentrations are rapidly suppressed in a large portion of CeH patients during the administration of L-T4 [24, 25].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [24]
Central hypothyroidism is easily diagnosed when free T4 is decreased and TSH levels are low or more often normal; dynamic testing is generally not necessary; T3 is still normal in most cases.
“In TBI patients, central hypothyroidism is easily diagnosed when levels of free T 4 are decreased and TSH levels are low or more often normal.Dynamic testing is generally not necessary because it does not add to diagnostic reliability.T 3 is still normal in most cases (210 -213).”
From Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach (2015) · cites this paper as [210]
Few studies have examined the use of liothyronine or other formulations of thyroid hormone for central hypothyroidism; there are no high-quality studies documenting superiority over levothyroxine in primary hypothyroidism, and there are potential safety concerns.
“Few studies have examined the use of L-T3 or other formulations of thyroid hormone for CH (80); there are no high-quality studies that document the superiority of these treatments over L-T4 in primary hypothyroidism, and there are potential safety concerns (reviewed in 76).”
From Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [76]
Even low doses of L-T4 are able to suppress TSH secretion.
“Even low doses of L-T4 are able to suppress TSH secretion (42, 59).”
From The diagnosis and management of central hypothyroidism in 2018 (2019) · cites this paper as [42]
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References 34 · Cited by 134
- Authors
- Ferretti, E., Persani, L., Jaffrain-Rea, M.-L., Giambona, S., Tamburrano, G., & Beck-Peccoz, P.
- Affiliations
- University of L'Aquila (IT)
- University of Milan (IT)
- the Department of Experimental Medicine (E. F., M.-L.J.-R.), University of L’Aquila, L’Aquila, Italy
- Sapienza University of Rome (IT)
- Institute of Endocrine Sciences (L.P., S.G., P.B.-P.), University of Milan, Ospedale Maggiore IRCCS, Istituto Auxologico Italiano IRCCS, and Istituto Clinico Humanitas, Milan
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1999-03-01
- Volume
- 84
- Issue
- 3
- Pages
- 924-929
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2096057448
- Cited by
- 134
- References
- 34
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 9 · 2013: 6 · 2012: 7
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Johnson and Johnson
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- central hypothyroidism, levothyroxine replacement therapy, treatment adequacy, free thyroxine, free triiodothyronine, thyroid-stimulating hormone, thyroid hormone action, soluble interleukin-2 receptor, overtreatment, undertreatment, dose adjustment
- MeSH terms
- Adult, Evaluation Studies as Topic, Female, Humans, Hypothyroidism, Male, Middle Aged, Prospective Studies, Thyroid Hormones, Thyroxine, Hormone Replacement Therapy
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