Switching from the tablet to the powder formulation of levothyroxine corrects severe hypothyroidism in a patient with lactose intolerance.

We describe a case of a 38-year-old woman who, after radioactive iodine therapy for Graves' disease, developed severe hypothyroidism despite receiving a high dose of levothyroxine (L-T4) tablet as replacement therapy. Her thyroid stimulating hormone (TSH) remained to be high despite the dose of L-T4 tablets to 400 µg/day after treatment for hypothyroidism, and the patient complained of general malaise and edema of the legs. Reduced intestinal absorption of L-T4 is the most common cause of failure to achieve the therapeutic target in hypothyroid patients receiving replacement therapy. She was admitted to our hospital for severe hypothyroidism due to resistance to treatment with L-T4 tablet. Our patient was found to have lactose intolerance (LI) by a detailed examination during hospitalization. Therefore, we assumed that LI was impairing intestinal absorption of L-T4 tablet in our patient, leading to severe hypothyroidism. The patient was switched to the powder formulation of L-T4 at the same daily dose, and serum levels of thyroid-stimulating hormone and thyroid hormones normalized. This is the case in which hypothyroidism due to reduced absorption of L-T4 tablet in a patient with LI was resolved by switching to L-T4 powder formulation.

Transducin ß-like 1, X-linked and nuclear receptor co-repressor cooperatively augment the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors.

Mutations in TBL1X, a component of the nuclear receptor co-repressor (N-CoR) and silencing mediator of retinoic acid and thyroid hormone receptor co-repressor complexes, have recently been implicated in isolated central hypothyroidism (CeH). However, the mechanisms by which TBL1X mutations affect negative feedback regulation in the hypothalamus-pituitary-thyroid axis remain unclear. N-CoR was previously reported to paradoxically enhance the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors (TR) in cell culture systems. We herein investigated whether TBL1X affects the unliganded TR-mediated stimulation of the promoter activities of genes negatively regulated by T3 in cooperation with N-CoR. In a hypothalamic neuronal cell line, the unliganded TR-mediated stimulation of the TRH gene promoter was significantly enhanced by co-transfected TBL1X, and the co-transfection of TBL1X with N-CoR further enhanced promoter activity. In contrast, the knockdown of endogenous Tbl1x using short interfering RNA significantly attenuated the N-CoR-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of N365Y or Y458C, TBL1X mutants identified in CeH patients, showed impaired co-activation with N-CoR for the ligand-independent stimulation of the TRH promoter by TR. In the absence of T3, similar or impaired enhancement of the TSHß gene promoter by the wild type or TBL1X mutants, respectively, was observed in the presence of co-transfected TR and N-CoR in CV-1 cells. These results suggest that TBL1X is needed for the full activation of TRH and TSHß gene promoters by unliganded TR. Mutations in TBL1X may cause CeH due to the impaired up-regulation of TRH and/or TSHß gene transcription despite low T3 levels.

Hypercalcemia after the Discontinuation of Medroxyprogesterone Acetate.

A 39-year-old woman was admitted to our hospital with symptoms of general fatigue, nausea, and vomiting that appeared three months after she stopped seven years of medroxyprogesterone acetate (MPA) medication for endometrial stromal sarcoma. Laboratory tests demonstrated moderate hypercalcemia. Several tests demonstrated that she was suffering from adrenal insufficiency. Glucocorticoid supplementation decreased her calcium level to a normal range, indicating that hypercalcemia was induced by adrenal insufficiency. It was suggested that she was suffering from MPA-induced adrenal insufficiency, but hypocortisolemia was being compensated by a high dose of MPA; hypocortisolemia and hypercalcemia then became evident after MPA treatment was discontinued.

NR4A1 (Nur77) mediates thyrotropin-releasing hormone-induced stimulation of transcription of the thyrotropin ß gene: analysis of TRH knockout mice.

Thyrotropin-releasing hormone (TRH) is a major stimulator of thyrotropin-stimulating hormone (TSH) synthesis in the anterior pituitary, though precisely how TRH stimulates the TSHß gene remains unclear. Analysis of TRH-deficient mice differing in thyroid hormone status demonstrated that TRH was critical for the basal activity and responsiveness to thyroid hormone of the TSHß gene. cDNA microarray and K-means cluster analyses with pituitaries from wild-type mice, TRH-deficient mice and TRH-deficient mice with thyroid hormone replacement revealed that the largest and most consistent decrease in expression in the absence of TRH and on supplementation with thyroid hormone was shown by the TSHß gene, and the NR4A1 gene belonged to the same cluster as and showed a similar expression profile to the TSHß gene. Immunohistochemical analysis demonstrated that NR4A1 was expressed not only in ACTH- and FSH- producing cells but also in thyrotrophs and the expression was remarkably reduced in TRH-deficient pituitary. Furthermore, experiments in vitro demonstrated that incubation with TRH in GH4C1 cells increased the endogenous NR4A1 mRNA level by approximately 50-fold within one hour, and this stimulation was inhibited by inhibitors for PKC and ERK1/2. Western blot analysis confirmed that TRH increased NR4A1 expression within 2 h. A series of deletions of the promoter demonstrated that the region between bp -138 and +37 of the TSHß gene was responsible for the TRH-induced stimulation, and Chip analysis revealed that NR4A1 was recruited to this region. Conversely, knockdown of NR4A1 by siRNA led to a significant reduction in TRH-induced TSHß promoter activity. Furthermore, TRH stimulated NR4A1 promoter activity through the TRH receptor. These findings demonstrated that 1) TRH is a highly specific regulator of the TSHß gene, and 2) TRH mediated induction of the TSHß gene, at least in part by sequential stimulation of the NR4A1-TSHß genes through a PKC and ERK1/2 pathway.