scholarly journals Therapeutic Concentrations of Mitotane (o,p′-DDD) Inhibit Thyrotroph Cell Viability and TSH Expression and Secretion in a Mouse Cell Line Model

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2453-2461 ◽  
Author(s):  
Maria Chiara Zatelli ◽  
Erica Gentilin ◽  
Fulvia Daffara ◽  
Federico Tagliati ◽  
Giuseppe Reimondo ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cell Viability ◽  
Cell Line ◽  
Secretory Activity ◽  
Mouse Cell ◽  
Therapeutic Window ◽  
Free T4 ◽  
Central Hypothyroidism ◽  
Time Treatment ◽  
Short Time

Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T4, and free T3 levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TαT1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TαT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.

scholarly journals Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

2013 ◽  
Vol 218 (3) ◽  
pp. 275-285 ◽  
Author(s):  
Erica Gentilin ◽  
Federico Tagliati ◽  
Massimo Terzolo ◽  
Matteo Zoli ◽  
Marcello Lapparelli ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Line ◽  
Primary Cultures ◽  
Pituitary Cell ◽  
Therapeutic Window ◽  
Adrenocortical Function ◽  
Acth Secretion ◽  
And Function ◽  
Acth Secreting ◽  
Human And Mouse

Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH-secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells.

scholarly journals Therapeutic Concentrations of Mitotane (o,p′-DDD) Inhibit Thyrotroph Cell Viability and TSH Expression and Secretion in a Mouse Cell Line Model

2010 ◽  
Vol 95 (5) ◽  
pp. 2514-2514
Author(s):  
Maria Chiara Zatelli ◽  
Erica Gentilin ◽  
Fulvia Daffara ◽  
Federico Tagliati ◽  
Giuseppe Reimondo ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Line ◽  
Mouse Cell ◽  
Line Model ◽  
Mouse Cell Line ◽  
Cell Line Model

scholarly journals Evaluation of the Adequacy of Levothyroxine Replacement Therapy in Patients with Central Hypothyroidism1

1999 ◽  
Vol 84 (3) ◽  
pp. 924-929 ◽  
Author(s):  
Elisabetta Ferretti ◽  
Luca Persani ◽  
Marie-Lise Jaffrain-Rea ◽  
Salvatore Giambona ◽  
Guido Tamburrano ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Replacement Therapy ◽  
Interleukin 2 ◽  
Hormone Action ◽  
Normal Range ◽  
Free T4 ◽  
Central Hypothyroidism ◽  
Thyroid Hormone Action ◽  
Daily Dose

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.

scholarly journals SAT-158 New Data on High Prevalence and Time of Occurrence of New Onset Hypothyroidism Associated with Mitotane Therapy in a Cohort of Adrenocortical Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jonathan Poirier ◽  
André Lacroix ◽  
Harold J Olney ◽  
Isabelle Bourdeau
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Function ◽  
Adrenocortical Cancer ◽  
Free T4 ◽  
Central Hypothyroidism ◽  
Number Of Patients ◽  
Secondary Hypothyroidism ◽  
Second Year ◽  
New Onset

Abstract Context. Mitotane is a steroidogenesis inhibitor and an adrenocorticolytic drug used to treat adrenocortical cancer (ACC). Central hypothyroidism is recognized in mitotane-treated patients and recent data suggested that mitotane could have an inhibitory effect on TSH-secreting cells in the pituitary gland. Moreover, mitotane may lead to induction of thyroid hormone metabolism. Clinical data on hypothyroidism related to mitotane such as prevalence and time of occurrence was described in a limited number of patients. Objective. To better characterize clinically secondary hypothyroidism in patients with ACC treated with mitotane therapy. Methods. We reviewed retrospectively paper charts and electronic records from patients with histologically confirmed diagnosis of ACC evaluated at our center from 1995-2019. We analysed the pattern of TSH and thyroid function, but also mitotane timing and levels at baseline and during treatment of patients under mitotane therapy. Thyroid hormone assessment including TSH, FT4 and FT3 was performed at least every 3 months during follow-up. Results. Our cohort of 104 patients with ACC includes 84 patients that received mitotane therapy. Among them, thyroid function data was incomplete for 39 cases. Complete data was retrieved from 45 patients. Ten out of 45 (22.2%) patients were already known for primary hypothyroidism and were receiving L-T4 replacement before the initiation of mitotane. Two of 45 (4.4%) patients maintained a normal thyroid function during complete follow up (4.5 years) and 33/45 (73.3%) had new onset hypothyroidism requiring levothyroxine treatment. Of these 33 patients, 22 were females and 11 were males, ranging from 22-74 yo with a median of 46 yo. The number of patients with ENSAT stage I, II, III and IV of disease were 1, 8, 11 and 13 respectively. Thyroid profiles were compatible with central hypothyroidism (low T4 with low or inappropriately normal TSH) in 22/33 patients (66.7%). Interestingly, 6/33 patients (18.2%) developed a TSH elevation with a normal lower-limit or low T4 level. The timeline distribution of the occurrence of hypothyroidism was 21.2% (n:7) at <3 months, 15.2% (n:5) between 3-6 months, 21.2% (n:7) between 6-9 months and 15.2% (n:5) between 9-12 months. 9.1% (n:3) occurred within the second year of treatment (between 12-24 months). However, in 5/33 (15.2%) cases, the exact time of new hypothyroidism onset was undetermined. Conclusion. Mitotane therapy is frequently associated with new onset hypothyroidism with a prevalence of 73% in our cohort of exposed patients and is most likely of central etiology. 72.7% of cases occur in the first year of treatment while 9.1% occur in the second year. This study supports the importance of monitoring thyroid function (including a free T4 level) during the complete course of mitotane therapy.

scholarly journals High-Dose Thyroid Hormone Replacement in Bexarotene-Induced Central Hypothyroidism

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A933-A933
Author(s):  
Tony Mathews ◽  
Benjamin Gigliottie
Keyword(s):  
Thyroid Hormone ◽  
Hormone Replacement ◽  
High Dose ◽  
Free T4 ◽  
Hormone Production ◽  
Central Hypothyroidism ◽  
Independent Manner ◽  
Current Case ◽  
Low T3 ◽  
Selective Ligand

Abstract Background: Central hypothyroidism is a rare disorder characterized by a defect in thyroid hormone production by an otherwise normal thyroid gland due to decreased stimulation by TSH. Medications are an uncommon cause. Case Presentation: A 72-year-old man was referred for evaluation of a low TSH. He had a long history of hypothyroidism, euthyroid on levothyroxine, and was diagnosed with cutaneous T cell lymphoma (CTCL). Due to disease progression on dapsone, PUVA and TAR baths, he was started on bexarotene. Soon after, he developed recurrent symptoms of hypothyroidism including fatigue, cold intolerance, dry skin, and myalgias. Workup revealed a TSH of <0.01 ulU/mL (0.27-4.20) with a free T4 of 0.6 ng/dl (0.9-1.7). After evaluation, his levothyroxine dose was increased. Repeat labs 3 months later showed a TSH of <:0.01 with a free T4 0.8 ng/dl and T3 43 ng/dl (80-200). Over several months, levothyroxine titration to a supraphysiologic dose of 800 mcg daily was required, despite optimal administration, to normalize FT4. Given persistent hypothyroid symptoms and a low T3 level, liothyronine 5 mcg BID was added and resulted in clinical and biochemical euthyroidism. Clinical Lessons: Unlike in primary thyroid disorders, the TSH assay is unreliable in central hypothyroidism since values can be low, normal, or even mildly elevated; regardless, TSH has subnormal bioactivity. Ineffectual TSH leads to a low T4, which is a required for diagnosis. Bexarotene, a derivative of Vitamin A, is a retinoid X receptor (RXR) selective ligand approved for the treatment of CTCL. The exact mechanism of bexarotene-induced thyroid dysfunction is not clear, although it involves both central and peripheral effects. Bexarotene inhibits TSH gene expression by decreasing the activity of the thyrotropin β subunit gene promoter in a dose-dependent and thyroxine-independent manner; TSH levels drop as early as 4-8 hours after exposure. Bexarotene also directly lowers T4 and T3 levels, even in athyreotic patients, by negatively impacting deiodinase activity and hepatic conjugation. Stopping bexarotene is often not possible given its effectiveness in CTCL. Therefore, thyroid hormone should be initiated with the goal of achieving a normal FT4, although as the current case demonstrates, massively supraphysiologic doses and/or the addition of liothyronine may be necessary to achieve clinical euthyroidism.

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