When Cancer Immunotherapy Silences the Thyroid Twice: A Rare One-Two Endocrine Blow

Immunotherapy has transformed the outlook for many cancers, but it comes with a paradox: the same drugs that unleash T cells against tumors can also turn them against the body’s own organs. A case report published in Frontiers in Oncology documents one of the strangest endocrine sequences yet seen with pembrolizumab, a widely used PD-1 checkpoint inhibitor. A 56-year-old man with esophageal squamous cell carcinoma developed not one but two distinct forms of hypothyroidism in succession, first from immune destruction of the thyroid gland itself and then, remarkably, from apparent failure of the pituitary gland that controls it.

The story began three years before his cancer diagnosis. A routine health examination in 2019 had revealed mild thyroid dysfunction: low total thyroxine (TT4) and total triiodothyronine (TT3), yet a thyroid-stimulating hormone (TSH) level that sat squarely within the normal range. Antibodies against thyroid peroxidase and thyroglobulin, the molecular fingerprints of autoimmune thyroid attack, were dramatically elevated at 1385 and 105 IU/mL respectively, and thyroid ultrasound pointed to Hashimoto’s thyroiditis. Nothing was done at the time, and the patient was not on thyroid hormone replacement when he was diagnosed with middle thoracic esophageal squamous cell carcinoma in April 2022.

On April 15, 2022, he began neoadjuvant therapy combining pembrolizumab with nab-paclitaxel and carboplatin, given every 21 days. Three weeks after the first pembrolizumab dose, his thyroid hormones surged: TT3 climbed to 5.27 nmol/L and TT4 to 164.49 nmol/L while TSH collapsed below the detection limit. This pattern of thyrotoxicosis is the classic opening act of painless thyroiditis, an immune-mediated inflammation in which damaged follicles dump preformed hormone into the bloodstream. Three weeks later the storm reversed, and his thyroid function crashed into overt hypothyroidism, with TT3 at 0.62 nmol/L and TT4 at 14.31 nmol/L while TSH rose to 6.032 mIU/L. Levothyroxine replacement at 50 micrograms daily was started.

Thyroid dysfunction is the most common endocrine immune-related adverse event of PD-1 inhibitors, with reported incidences of 7.0 to 8.5 percent for PD-1 monotherapy and up to 13.2 percent for combination regimens such as nivolumab plus ipilimumab. The prevailing explanation is destructive thyroiditis: PD-L1 and PD-L2 are abundantly expressed on thyroid follicular cells, which may make the gland uniquely vulnerable when checkpoint inhibition removes the brakes on systemic T-cell responses. Typically, a transient hyperthyroid phase precedes permanent hypothyroidism as the gland is progressively destroyed. Patients with pre-existing positive thyroid peroxidase antibodies, as in this case, face a significantly higher risk of developing these events.

What followed was anything but typical. After esophagectomy in July 2022 and further adjuvant chemotherapy, the patient’s TSH climbed to 119.96 mIU/L despite escalating levothyroxine doses, and his thyroid function eventually stabilized on 100 micrograms daily. But at week 31 of pembrolizumab therapy, in November 2022, follow-up testing showed something unexpected: TSH began to fall, dropping below the reference range and eventually to the lower limit of detection, while TT4 fell in parallel. In a patient whose thyroid had been destroyed, a low TSH with low thyroid hormone cannot be explained by the gland itself. It pointed instead to a failing pituitary, the master gland that should be screaming TSH to drive whatever thyroid tissue remains.

When he was referred to endocrinology in March 2023 for profound fatigue and myxedema, the team systematically probed the other pituitary axes. Morning cortisol was normal at 179.64 ng/mL with preserved diurnal rhythm and only mildly elevated ACTH, indicating intact adrenal function. Follicle-stimulating hormone was mildly raised, but the remaining gonadal hormones were normal, and there was no hyponatremia or evidence of diabetes insipidus. Pituitary MRI showed a thinned gland, just 3.5 mm in height, with homogeneous signal, uniform contrast enhancement, no stalk deviation, and no mass lesion. The diagnosis: isolated central hypothyroidism, a condition in which the pituitary’s TSH secretory capacity fails while every other hormonal axis remains intact.

Central hypothyroidism arising after painless thyroiditis and primary hypothyroidism in the same PD-1 inhibitor-treated patient has essentially not been described before. Immune-related hypophysitis, inflammation of the pituitary, occurs in only 0.5 to 1 percent of patients on PD-1 agents and typically emerges late in therapy, with a median onset around 26 weeks, predominantly in older men, often without headache and sometimes with unremarkable imaging. Those features fit this case. But almost all previously documented cases of checkpoint inhibitor hypophysitis involve adrenocortical insufficiency, and hypophysitis presenting exclusively with isolated TSH deficiency has never been reported. Over four years of follow-up, this patient’s adrenal, gonadal, and posterior pituitary function remained intact, while his TSH stayed persistently suppressed, suggesting sustained impairment of the pituitary’s TSH secretory reserve rather than a transient insult.

The authors reconstruct the course in three phases. Before pembrolizumab, the patient already had Hashimoto’s thyroiditis with low TT4 but normal TSH, hinting that mild central hypothyroidism may have predated immunotherapy. In the second phase, destructive thyroiditis produced severe primary hypothyroidism, and notably the compensatory TSH rise was smaller than expected for the degree of free T4 reduction, a subtle clue of a suboptimal pituitary response. In the final phase, with the thyroid pharmacologically controlled, TSH declined progressively to undetectable levels alongside falling TT3 and TT4. The researchers speculate that on the background of pre-existing Hashimoto’s disease and possible subclinical central hypothyroidism, pembrolizumab may have triggered delayed pituitary injury, or perhaps exacerbated a pre-existing lesion rather than initiating it outright.

The case also exposed a practical dosing dilemma rarely discussed in the literature. Levothyroxine is absorbed mainly in the jejunum, and this patient’s post-esophagectomy gastrointestinal remodeling had altered his intestinal anatomy and drug exposure. His dose was titrated to 175 micrograms daily, a figure exceeding the conventional replacement dose for men after total thyroidectomy in the region, yet his total T4 remained mildly low. Switching to a split regimen of 50 micrograms three times daily improved hormone levels, though subsequent monitoring showed recurrent mild free T4 elevations, underscoring how variable bioavailability can be after upper gastrointestinal surgery. For the growing population of cancer survivors living with both esophagectomy and checkpoint inhibitor endocrinopathy, personalized dosing schedules may be essential.

The report carries honest limitations: it is a single retrospective case, the TRH stimulation test was not performed to formally assess pituitary reserve, no biopsy was obtained, and no baseline pituitary MRI existed for comparison. The 15-week gap between the onset of TSH decline and complete pituitary evaluation also means any acute-phase pituitary enlargement, which can appear and resolve within weeks in immune hypophysitis, would have been missed. Even so, the biochemical trajectory, imaging findings, and management challenges offer a valuable lesson for oncologists and endocrinologists alike. Thyroid dysfunction during PD-1 inhibitor therapy is common and usually straightforward, but this case is a reminder that the pituitary can also fall silent, sometimes in isolation, and that pituitary function deserves monitoring alongside the thyroid when checkpoint inhibitors are on board.

Subject of Research: Sequential primary and central hypothyroidism as immune-related adverse events of pembrolizumab therapy

Article Title: Pembrolizumab-associated primary hypothyroidism followed by central hypothyroidism: a case report

Article References: Sun, J., Wang, C., Sun, Z., & Li, W. (2026). Pembrolizumab-associated primary hypothyroidism followed by central hypothyroidism: a case report. Frontiers in Oncology, 16, Article 1978296. https://doi.org/10.3389/fonc.2026.1978296

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1978296

Keywords: pembrolizumab, PD-1 inhibitors, immune checkpoint inhibitors, hypothyroidism, central hypothyroidism, Hashimoto's thyroiditis, painless thyroiditis, hypophysitis, immune-related adverse events, levothyroxine, esophageal cancer, pituitary dysfunction