ENDOCRINE SOCIETY
OXFORD
Central Hypothyroidism is Frequent During Mitotane Therapy in Adrenocortical Cancer Patients: Prevalence and Timeline
Jonathan Poirier, 10 Sophie Godemel,2 Aurelie Mourot, 10D Solange Grunenwald,2(D Harold J. Olney,3 Xuan Kim Le,1 Andre Lacroix, 10D Philippe Caron,2D and Isabelle Bourdeau1D
1Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, H2X 3E4, Canada
2Service d’Endocrinologie, Maladies métaboliques et Nutrition, Pôle Cardio-Vasculaire et Métabolique, Centre Hospitalo-Universitaire de Toulouse, 31059 Toulouse Cedex, France
3Oncology Division, Department of Medicine and Research Center, Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, H2X 3E4, Canada
Correspondence: Isabelle Bourdeau, MD, Division of Endocrinology, Department of Medicine, CRCHUM, B10.8074, 1000 Rue Saint-Denis, Montréal, Québec, H2X OC1, Canada. E-mail: isabelle.bourdeau@umontreal.ca.
Abstract
Context: Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence are limited.
Objective: To better characterize thyroid hormone insufficiency in patients exposed to mitotane.
Methods: We reviewed medical records of patients from 2 academic centers in Montreal (Canada) and Toulouse (France) with exposure to mitotane therapy for adrenocortical cancer between 1995 and 2020. We analyzed the thyroid function parameters during and after treatment.
Results: In our cohort of 83 patients, 17 were excluded because of preexisting primary hypothyroidism or drug-induced hypothyroidism. During follow-up, 3/66 patients maintained a normal thyroid function and 63/66 developed central hypothyroidism. Among those 63 patients, 56 presented with an inappropriately normal or low TSH and 7 with a mildly elevated TSH. The onset of hypothyroidism was: < 3 months in 33.3%, 3 to 6 months in 19.1%, 6 to 9 months in 14.3%, and 9 to 12 months in 9.5%. At least 14.3% of cases occurred after 12 months of exposure, and 6 patients had an undetermined time of occurrence. Over time, 27 patients stopped mitotane and partial (42.3%) or complete (23.1%) recovery from hypothyroidism was observed, mainly in the first 2 years after mitotane discontinuation.
Conclusion: Mitotane therapy is frequently associated with new onset of central hypothyroidism with a prevalence of 95.5%. Most cases occurred in the first year of treatment. Partial or full recovery of thyroid function occurs in 65.4% of cases. This study supports the importance of systematic monitoring of TSH and free T4 levels during and following discontinuation of mitotane therapy.
Key Words: adrenocortical cancer, mitotane, hypothyroidism
Abbreviations: ACC, adrenocortical cancer; HPA, hypothalamic-pituitary-adrenal; TPO, thyroid peroxidase.
Adrenocortical cancer (ACC) is a rare but aggressive neoplasia with a poor prognosis, especially when diagnosed at later stages. The estimated incidence of the disease is 0.7 to 2 patients per million per year (1). Previous studies evaluating treatment with adjuvant mitotane, an adrenolytic drug, have demon- strated its usefulness for preventing recurrence and prolonging the disease-free interval after surgery in patients at high risk of recurrence, although not in those with a lower risk as demon- strated by the ADIUVO trial (2-4). This agent also acts as a po- tent steroidogenesis inhibitor and is associated with many metabolic and hormonal side effects such as adrenal insuffi- ciency, hypogonadism, hypothyroidism, and dyslipidemia (5-8). Interestingly, mitotane-induced hypothyroidism has been repeatedly observed over the past decades, and its under- lying mechanism has generated multiple hypothesis, but to this
day, few clinical data have been published on the matter. In this study, we therefore present new clinical data on thyroid profile from our cohort of patients with ACC treated with mitotane.
Methods
This retrospective cohort study was conducted in 2 large refer- ral centers for adrenal diseases in Montreal, Canada, and Toulouse, France: Centre Hospitalier de l’Université de Montréal and Centre Hospitalo-Universitaire de Toulouse. After obtaining institutional ethical committee approval (CHUM: CE2010-304, 09.244, CHU de Toulouse: RnIPH2022-03), data were retrieved from patient’s paper and electronic files from 1995 to January 2020. Patients were included in the study using the following criteria: aged
18 years or older, diagnosis of ACC based on pathology report or biochemical and radiological studies, mitotane treatment exposure, availability of thyroid hormone profile, and mito- tane serum dosage during therapy at a minimal interval of 4 months. Patients were excluded if hormonal profiles were not available, if they had preexisting hypothyroidism, or if they were taking drugs known to alter thyroid hormonal pro- file other than corticosteroids.
Data collection included patient demography, tumor size, hormonal secretion, duration of adjuvant mitotane therapy, cumulative dose of mitotane during course, mitotane serum levels, thyroid hormonal profile (TSH, free T4, and total T3/ free T3) and antithyroid peroxidase (TPO) antibody status (if available). Mitotane blood concentration was determined by HPLC in both centers and was considered therapeutic when a target of 14 to 20 mg/L was reached. TSH, free T4, free T3, and anti-TPO levels were measured using immuno- assay method. Because follow-up was done in an outpatient setting (in Montreal), many patients had their blood drawn and analyzed in several peripheral hospital laboratories. Every patient from the Toulouse cohort had their blood tests performed in a single center. Mitotane serum concentration measurement was performed at the same laboratory in all pa- tients in each center.
Thyroid function test interpretation was always performed based on the provenance laboratory’s reference values because immunoassays may differ in peripheral centers. Following in- terpretation of laboratory values, central hypothyroidism was diagnosed based on recent European Thyroid Association guidelines using the following criteria: (1) low free T4 associ- ated with low or normal TSH values or (2) free T4 reduction of >20% from base values (9). All cases were then classified in 3 different groups based on their TSH serum level: mildly ele- vated (<10 mUI/L), inappropriately normal, or lower than normal.
Patient characteristics were expressed using descriptive sta- tistics and the mean changes in time for hormonal laboratory values were assessed via t test. Statistical calculations were made using Analysis ToolPak and Solver-Microsoft Excel 365 version 16.65 (2022).
Results
In our cohort, a total of 83 ACC-treated patients were exposed to mitotane therapy and had sufficient retrievable data to meet the inclusion criteria for this study. After review, a total of 16 pa- tients with preexisting hypothyroidism and 1 patient with neomercazole-induced hypothyroidism were excluded from the main analysis. In total, 3 patients maintained a normal thy- roid function during mitotane therapy, despite having reached a significant therapeutic dose and exposure, whereas 63 cases ex- perienced a new-onset hypothyroidism including 20 males and 46 females with a mean and median age of 49.6 and 49.5 years, respectively. The number of patients with European Network for the Study of Adrenal Tumors stage I, II, III, and IV of disease were 4, 25, 17, and 17 respectively (3 unknown). Tumor hor- monal secretion profiles were as follows: 10/48 (20.8%) had a nonsecreting tumor, 21/48 (43,8%) had combined cortisol and androgen secretion, 12/48 (25.0%) had a cortisol-secreting tumor and 5/48 (10.4%) had an androgen-producing tumor. The remaining 18 patients had an unknown secretory profile. Regarding cancer therapy, all patients were treated with mito- tane, but 20 also received simultaneous chemotherapy such as
doxorubicin, etoposide, carboplatin, streptozocin, gemcitabine, or Taxotere. The dose range for daily hydrocortisone replace- ment was 15 to 100 mg with a mean of 48 mg. The mean serum concentration of mitotane at the onset of hypothyroidism was 11.87 mcg/L and the mean and median cumulative doses of mi- totane were 593 and 325 g (range, 14-4147), respectively (Table 1). TPO antibody testing was performed in only 4 pa- tients and the only positive patient had a lower limit TSH value with low free T4. Based on the data from the 31 patients from Toulouse, the average values of weight and levothyroxine re- placement dose were 68.1 kg, 121 mcg, and 1.80 mcg/kg, re- spectively. The corresponding median values were 64 kg, 112.5 mcg, and 2.01 mcg/kg, respectively. Unfortunately, these data were not available for the 35 patients from Montreal.
Thyroid profiles were measured systematically every 3 to 4 months during follow-up, although this interval increased to 6 months after 2 years of mitotane treatment in the 31 patients from Toulouse. Among the 63 patients with new onset of
| % of cohort | ||
|---|---|---|
| Sex, n | ||
| Male | 18 | 28.6 |
| Female | 45 | 71.4 |
| Median age, y | 50 | |
| ENSAT stage, n | ||
| I | 4 | 6.3 |
| II | 24 | 38.1 |
| III | 17 | 27.0 |
| IV | 15 | 23.8 |
| Unknown | 3 | 4.8 |
| Tumor hormonal profile, n | ||
| No secretion | 8 | 12.7 |
| Cortisol | 12 | 19.0 |
| Androgen | 5 | 7.9 |
| Combined cortisol and androgens | 20 | 31.8 |
| Unknown | 18 | 28.6 |
| TSH value at onset of central hypothyroidism, n | ||
| Mildly elevated | 7 | 11.1 |
| Inappropriately normal | 48 | 76.2 |
| Low | 8 | 12.7 |
| Delay of onset after start of mitotane, mo | ||
| <3 mo | 21 | 33.3 |
| 3 to <6 mo | 12 | 19.1 |
| 6 to <9 mo | 9 | 14.3 |
| 9 to <12 mo | 6 | 9.5 |
| 12 mo+ | 9 | 14.3 |
| Undetermined | 6 | 9.5 |
| Mean mitotane serum concentration at central hypothyroidism onset, mcg/L | 11.87 | |
| Median cumulative mitotane dose at central hypothyroidism onset, g | 325 |
Description of baseline characteristics of patients at the time of central hypothyroidism’s diagnosis. Abbreviation: ENSAT, European Network for the Study of Adrenal Tumors.
Preserved thyroid function n = 3
Mildly elevated TSH n = 7
New onset central hypothyroidism n = 63
Inappropriatly normal TSH n = 48
ACC patients treated with mitotane n = 83
Low TSH n = 8
Excluded patients n =17
-Pre-existing primary hypothyroidism (16) -Drug-induced hypothyroidism (1)
central hypothyroidism, thyroid profile analysis showed that 48/63 (76.2%) had a pattern of inappropriately normal TSH, 8/63 (12.7%) had a low TSH value, and 7/63 (11.1%) had a mildly elevated TSH value (Fig. 1). In the combined groups of patients with a normal or low TSH, 53/56 presented with an initially lower than normal free T4, and the remaining 3/56 maintained both normal free T4 and TSH values while experiencing a >20% free T4 drop from baseline. The delay for onset of new hypothyroidism after introduction of mito- tane therapy was reviewed for each patient and distributed as follow: < 3 months in 33.3% (n = 21), 3 to 6 months in 19.1% (n = 12), 6 to 9 months in 14.3% (n = 9), and 9 to 12 months in 9.5% (n = 6). At least 14.3% (n = 9) occurred after the first year of exposure, the longest being after 48 months, and 6/63 (9.5%) had an undetermined time of occur- rence. Thus, a total of 48/63 (76.2%) developed hypothyroid- ism during the first year of mitotane therapy.
Laboratory result variations from baseline to hypothyroid- ism diagnosis were as follows: TSH value changed from 2.33 ± 0.95 to 5.77 ± 0.34 µUI/L (P <. 001) in the group with mild- ly elevated TSH, from 2.10 ±0.38 to 2.04 + 0.29 µUI/L (P =. 802) in the group with inappropriately normal TSH, and from 0.48 ± 0.27 to 0.39 ± 0.15 µUI/L (P =. 512) in the group with low TSH. Free T4 value changed from 13.03 ± 3.16 to 9.63 ± 0.97 nmol/L (P =. 04) in the group with mildly elevated TSH, from 12.69 ±0.67 to 8.58 ±0.31 nmol/L (P <. 001) in the group with inappropriately normal TSH, and from 11.68 ± 1.28 to 8.91 ± 0.87 nmol/L (P <. 001) in the group with low TSH (Fig. 2). The mean time interval between mitotane exposure and hypothyroidism onset for each group ranged from 4.5 to 9.0 months, but the variation between groups was not statistically significant. Mean mito- tane cumulative doses at hypothyroidism diagnosis were, respectively, 1101 ± 484 g, 457 ± 152 g, and 835 ±1706 g.
A total of 27 patients successfully stopped adjuvant mito- tane, 24 after completion of planned therapy, 1 from side
effects, and 2 for other or unknown reasons. Over time, 7/27 (25.9%) of those patients fully recovered from hypothy- roidism and levothyroxine supplementation was no longer ne- cessary. Another group of 9/27 (33.3%) patients achieved a partial recovery showed by a reduction in levothyroxine re- placement requirement of at least 25 mcg daily without con- current deterioration in thyroid function parameters. In 2 (7.4%) other patients, we also observed direct improvement in laboratory parameters despite maintaining the same levo- thyroxine dose. In 1 of those cases, the TSH and free T4 values changed from 3.41 to 0.54 µUI/L and from 8.6 to 12.8 nmol/L, respectively. In the second case, the corresponding values changed from 3.23 to 2.50 µUI/L and from 10.6 to 13.1 nmol/L, respectively. Most partial or complete recoveries were observed in the first 2 years (10 in the first year and 4 in the second year) following mitotane cessation. In this sub- group, total duration of mitotane therapy was between 4 and 114 months, with a mean and median duration of 39.8 and 31.0 months, respectively. This represents a similar treat- ment duration in comparison with the nonrecovery group, which had a mean and median duration of 40.4 and 35.0 months, respectively. Despite the large disparity in total dur- ation of treatment among patients, no association was made between frequency of hypothyroidism recovery and shorter or longer treatment duration. Additionally, the total cumula- tive dose of mitotane at the cessation of therapy ranged from 438 to 9401 g, with a mean and median of 2755 and 2228 g, respectively. In comparison, the nonrecovery group had a mean and median cumulative dose of 1732 and 1080 g, re- spectively. Patient characteristics for the recovery subgroup are described in Table 2.
Discussion
Findings from our cohort showed that a very large majority of patients developed onset of central hypothyroidism during
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6,00
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TSH (µUI/L)
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TSH (µUI/L)
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4,00
4,00
4,00
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3,00
3,00
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2,00
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Baseline
At diagnosis
Baseline
At diagnosis
Baseline
At diagnosis
*
19,00
19,00
19,00
Free T4 (nmol/L)
17,00
Free T4 (nmol/L)
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Free T4 (nmol/L)
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15,00
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13,00
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At diagnosis
mitotane therapy for ACC treatment. This prevalence is high- er than previously reported in the literature. In 2020, Basile et al reported new levothyroxine supplement requirement in 36.2% of their cohort of 69 patients without preexisting hypothyroidism (8). In the same year, Vikner et al published data from a Danish cohort of 50 patients in which new-onset hypothyroidism had a prevalence of 44% (10). In contrast, 2 studies described a very high prevalence of hypothyroidism during mitotane therapy (92.3%-100%), but both studies had a low number of patients (n = 13 and n = 9) (6, 11). A sys- tematic review by Bianchini et al recently estimated that mitotane-induced hypothyroidism had an overall prevalence
of 45.4%, based on accumulated data from 152 patients be- tween 1984 and 2020 (12). Those previous studies used a low free T4 level without compensatory TSH elevation as a diagnosis criterion for mitotane-induced hypothyroidism. Moreover, Basile et al also considered the introduction of lev- othyroxine replacement as an additional criterion. There were also differences in the frequency of hormonal screening among these studies. In comparison, the 2 largest cohort stud- ies (8, 10) monitored thyroid function with a minimal interval of 6 months, whereas the study with a lower number of pa- tients had a more frequent hormonal follow-up of 3 months (6). In summary, the notable difference in prevalence between
| ID | Sex Mor F | Age at diagnosis y | ACC stage I to IVª | Delay of onsetb mo | Mitotane duration mo | Cumulative dose g | Recovery delay mo | Levothyroxine dose mcg Initial Final | |
|---|---|---|---|---|---|---|---|---|---|
| MTL01 | F | 41 | 3 | 10 | 27 | 2745 | 37 | 125 | 100 |
| MTL05 | F | 34 | 4 | 8 | 15 | 2295 | 6 | 75 | 75 |
| MTL06 | M | 74 | 2 | 4 | 23 | 1748 | 35 | 100 | 0 |
| MTL09 | F | 35 | 1 | 4 | 25 | 1374 | 60 | 100 | 75 |
| MTL16 | F | 22 | 2 | 21 | 34 | NA | 6 | 50 | 0 |
| MTL28 | F | 60 | 2 | 1 | 34 | 3060 | 5 | 100 | 50 |
| MTL29 | M | 53 | 1 | 16 | 27 | NA | 14 | 0 | 0 |
| TOU08 | M | 49 | NA | 48 | 60 | 2160 | 60 | 225 | 175 |
| TOU16 | F | 27 | 3 | 10 | 38 | 3498 | 28 | 50 | 0 |
| TOU19 | F | 53 | 2 | 8 | 31 | 1063 | 11 | 75 | 0 |
| TOU28 | F | 31 | 2 | 46 | 108 | 9401 | 14 | 100 | 0 |
| TOU31 | F | 57 | 1 | 2 | 45 | 2450 | 28 | 200 | 150 |
| TOU32 | M | 42 | 2 | 3 | 42 | 3444 | 25 | 1875 | 150 |
| TOU33 | F | 48 | 2 | 2 | 24 | 1228 | 19 | 1625 | 100 |
| TOU35 | F | 54 | 2 | 1 | 36 | 1961 | 35 | 100 | 0 |
| TOU36 | M | 58 | 2 | 4 | 114 | 5913 | 32 | 175 | 1125 |
| TOU37 | F | 58 | 2 | 1 | 24 | 1309 | 11 | 75 | 0 |
| TOU39 | M | 54 | 2 | 2 | 4 | 438 | 2 | 100 | 75 |
Every line represents a different patient (ID in first column). Age and European Network for the Study of Adrenal Tumors stages are based on the date of adrenocortical cancer diagnosis. The data in other columns represent the timeline of appearance of central hypothyroidism from the introduction of mitotane (delay of onset) and the time between treatment interruption and partial or complete thyroid function recovery (recovery delay). Total mitotane duration is expressed in months alongside its cumulative dose in grams. Evolution of levothyroxine dosage requirement from diagnosis to complete or partial hypothyroidism recovery are shown in the last 2 columns.
ªAt initial diagnosis of adrenocortical cancer.
“Hypothyroidism onset after initiation of mitotane.
“Recovery delay after mitotane cessation.
those studies and ours could be a consequence of differences in criteria used to classify thyroid disorders and/or a difference in frequency of thyroid function screening.
Many hypotheses have previously been proposed to explain the underlying mechanisms of mitotane-induced abnormal thyroid parameters. Technical interference with measurement method is always a concern when evaluating hormone levels. However, findings of low total T4 and free T4 levels associ- ated with mitotane treatment has been reported consistently across many countries using different immunoassays. Also, no direct laboratory interference was observed in a study by Zatelli et al, despite directly measuring thyroid function pa- rameters in hypo-/hyper-/euthyroid patients serum exposed to variable concentrations of mitotane (7). This also goes against the previously suggested hypothesis of increased pro- tein binding (13, 14) because lower free T4 level caused by augmented binding to proteins should also cause a compensa- tory TSH level elevation and this phenomenon was not ob- served in most patients in our cohort. As shown in the results, use of high dose of corticosteroid is standard in patients exposed to mitotane and is a known thyroid function-altering factor. However, this effect alone cannot ex- plain the observed thyroid hormone profiles because free T4 should either be normal or elevated, which was contrary to our observations. In vitro direct pituitary toxicity by mitotane has previously been confirmed in a mouse TaT1 pituitary cell line. In their study, Zatelli et al demonstrated that mitotane in- hibits functional TSH expression and secretion by altering B-subunit gene transcription, while also reducing cell viability and inducing apoptosis at therapeutic levels. Another interest- ing finding is the decreased response of TSH-secreting pituit- ary cells to TRH stimulus and the persistence of this blunted response over a short time after removal of mitotane (7). These alterations in TSH expression mechanisms could theor- etically lead to a nonfunctional or lower activity/affinity form of TSH, which could explain its mild elevation in serum levels associated with lower free T4 levels observed in some patients.
Because approximately one-third of mitotane-exposed pa- tients received supplemental chemotherapy during follow-up, attention was also given to the possibility of chemotherapy- induced hypothyroidism. Among the chemotherapy agents used in our cohort, only sunitinib is known to induce hypothy- roidism in up to 33% (15, 16) of patients. In our cohort, 2 pa- tients were treated with sunitinib, but introduction of this agent was made after development of central hypothyroidism in both cases. Moreover, no specific pattern of hypothyroid- ism onset was observed in patients exposed to other chemo- therapy agents.
In the hypothyroidism group with low TSH values, a curi- ous finding was that baseline value for 4/8 patients were al- ready <0.50 µUI/L despite having yet a normal free T4 level. Multiple hypotheses such as recent iodine or radiology con- trast agent exposure, depressive disorder, higher corticoster- oid replacement dose, recent surgery, increased severity of disease, or intensive care requirement were explored while re- viewing patient data, but no explanation or evidence support- ing these potential culprits could be found.
Complete or partial thyroid function recovery was achieved in approximately 65% of patients who had stopped mitotane treatment altogether. However, the delay for complete recov- ery after mitotane cessation was variable among patients with half of cases occurring in the first 2 years and the other half in the next 3 to 5 years of follow-up. Attention was given to the
total duration and cumulative dose of mitotane therapy for these patients and comparison to the nonrecovery group was made. Interestingly, the group with partial or complete thyroid function recovery was found to have a similar dur- ation and higher cumulative dose of treatment compared with the patients who maintained their hypothyroidism state. Thus, those 2 variables appear unlikely to be risk factors for prolonged hypothyroidism after mitotane therapy. Moreover, this finding is similar to hypothalamic-pituitary- adrenal (HPA) axis recovery parameters in our previous study, in which longer exposure to mitotane therapy did not affect the outcome of HPA axis recovery (17). In this context, it appears unlikely that higher cumulative dose or duration of mitotane therapy would predict absence or delay in hypothy- roidism recovery. Interestingly, because the delay for recovery of either HPA axis or thyroid function is often long in affected patients, the possibility of a delayed toxicity mechanism af- fecting the pituitary gland cells could possibly be explored in further studies.
Current expert guidelines (1) suggest that patients with clinical symptoms of hypothyroidism only should be given levothyroxine replacement to treat mitotane-induced hypo- thyroidism. In our cohort, levothyroxine was prescribed in pa- tients with new-onset hypothyroidism based on laboratory values regardless of symptomatic status. In all cases, normal free T4 values were achieved within 1 to 4 months of supple- mentation. There were no adverse effects or thyrotoxicosis- related complication reported by patients and clinicians in re- lation to this supplementation. Levothyroxine replacement benefits on quality of life or severity of symptoms was difficult to evaluate properly because of the presence of many con- founders such as side effects of mitotane or supplemental chemotherapy, glucocorticosteroid deficiency, and underlying ACC disease symptoms, which can also cause or increase fa- tigue, asthenia, loss of appetite, or gastrointestinal discomfort. To our knowledge, there are no published studies addressing this specific quality-of-life issue.
Previous data from Gagnon et al (2022) revealed that pa- tients treated for ACC with mitotane were subject to dyslipi- demia, manifested by a clinically significant elevation of lipid parameters (low-density lipoprotein cholesterol, high- density lipoprotein cholesterol, triglyceride, and non-high- density lipoprotein cholesterol) during the first year of treatment (18). Similar findings were observed in the Toulouse cohort (unpublished data). Because the relation be- tween thyroid and lipid profiles was not a focus of this study, it remains unclear whether dyslipidemia could also be a conse- quence of an underlying hypothyroidism, or lower free T4 hormone level caused by mitotane. A meta-analysis by Kotwal et al revealed that levothyroxine replacement therapy in overt and subclinical hypothyroidism showed significant improvements in the lipid profile of patients (19). However, because this was not researched in patients treated for ACC specifically, further studies are needed to explore the relation between mitotane treatment, dyslipidemia and underlying thyroid disorders, and the benefits of levothyroxine replace- ment in this context. In consideration of these data and given that nonspecific symptoms attributed to hypothyroidism often overlap with those of glucocorticoid deficiency, it could be hy- pothesized that optimizing thyroid hormone levels early dur- ing mitotane therapy could provide benefits on 2 fronts. Hypothyroidism supplementation could facilitate dyslipide- mia management while also potentially lessen the need for
increasing glucocorticoid dosage to alleviate nonspecific symptoms such as asthenia or fatigue.
The findings of our study remain exploratory based on its retrospective design. As expected, some files had incomplete data and could not be entirely recovered after thorough re- viewing, which could cause underestimation or overesti- mation of certain tendencies in outcomes. Also, the lack of centralization for laboratory analysis of thyroid function tests in 1 of the study centers added an additional challenge for the analysis of data. However, because every laboratory result was scrupulously interpreted according to its respective prov- enance laboratory reference values, we expect that this factor will have little impact on the validity of our findings.
To our knowledge, this study is the first attempt to thor- oughly evaluate onset of central hypothyroidism and its po- tential for recovery after mitotane cessation in a large cohort of patients with ACC. In a rare disease such as ACC, the col- laborative nature of this study strengthened the validity of our observations and helps to provide valuable and useful insight into endocrine complications of its most effective medical treatment.
In conclusion, this study confirmed that onset of central hypothyroidism is very frequent (>90% of patients) in pa- tients with ACC treated with mitotane and can occur during the first year of therapy in 3 of 4 patients. In patients able to fully stop mitotane, we observed a significant rate of complete or partial recovery of thyroid function, but this recovery pro- cess was very lengthy, spanning 1 to 5 years in most patients. These finding highlight the importance of maintaining regular thyroid function monitoring (including free T4 levels) during, but also after, cessation of mitotane therapy in patients with new onset of central hypothyroidism.
Funding
This study did not receive any funding.
Disclosures
The authors have nothing to disclose.
Data Availability
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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