DeCure for Selective pituitary resistance to thyroid hormone
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for selective pituitary resistance to thyroid hormone — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleSelective pituitary resistance to thyroid hormone maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for selective pituitary resistance to thyroid hormone is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
thyroid hormone receptor beta (THRB) — THRB is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 4-phenylphenoxydrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7WMH · 1.97 Å · ligand 2-[[1-methoxy-4-oxidanyl-7-(4-phenylphenoxy)isoquinolin-3-yl]carbonylamino]ethanoic acid (9II). Experimental structure, not a prediction.
What the evidence adds up to
A 2008 study of a single girl with selective pituitary resistance to thyroid hormone measured the effect of bromocriptine over more than seven years. Before treatment, her mean triiodothyronine (T3) was 2.44 nmol/l and her mean thyroid-stimulating hormone (TSH) was 4.81 mU/l. During bromocriptine therapy, T3 fell to 2.15 nmol/l and TSH to 1.59 mU/l. The product T3 × TSH, used as an index of pituitary resistance, dropped from 11.298 to 3.229 mU/l × nmol/l, a difference the authors report as statistically significant (p < 0.005). The authors conclude that bromocriptine should be considered as an initial treatment option for this condition.
The broader literature on thyroid hormone resistance syndrome, from 1994 and 1995, establishes that the disorder is rare, defined by elevated free thyroid hormones, inappropriately normal or raised TSH, and reduced peripheral tissue response. Mutations in the thyroid hormone receptor beta gene are found in both generalised resistance (GRTH) and pituitary resistance (PRTH), and the same mutation can produce different clinical pictures even within one family. The 1994 review notes that biochemical and physiological indices of thyroid hormone action lack precision and overlap between the two subtypes, and that clinical signs can vary over time in the same patient without correlating with subjective symptoms.
The 2001 review summarises that thyroid hormones act through nuclear receptors that are ligand-regulated transcription factors, and that resistance to thyroid hormone is one of the conditions illuminated by genetically engineered mouse models. The 1995 paper explains that hormone-resistance syndromes, including resistance to thyrotropin caused by mutations in the TSH receptor or its coupled G protein, result from defects in receptors or post-receptor pathways.
What remains missing is any controlled trial of bromocriptine in a larger group of patients with selective pituitary resistance, any comparison with other agents such as triiodothyroacetic acid or somatostatin analogues, and any prospective stratification by genotype or by the temporal variability in symptoms and biochemical markers that the 1994 review documents. The single-patient study provides no data on long-term clinical outcomes such as goitre size, heart rate, or quality of life.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Physiological Reviews · 2001 · 2011 citations
Physiological and Molecular Basis of Thyroid Hormone Action
AbstractThyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.
New England Journal of Medicine · 1995 · 347 citations · open access
Resistance to Thyrotropin Caused by Mutations in the Thyrotropin-Receptor Gene
AbstractHormone-resistance syndromes can be broadly defined as conditions resulting from reduced or absent end-organ responsiveness to biologically active hormones. They are caused by defects in hormone receptors or post-receptor defects.1–3 Mutations in the thyroid hormone–receptor β gene cause resistance to thyroid hormone, which is characterized by elevated serum thyroid hormone concentrations with few or no clinical and biochemical manifestations of thyroid hormone excess and, most notably, normal or slightly increased thyrotropin secretion.1 Mutations that inactivate the thyrotropin receptor or the G (guanine nucleotide–binding) protein that couples the receptor to adenylate cyclase should cause thyrotropin resistance, resulting in either hypothyroidism . . .
The Variable Clinical Phenotype in Thyroid Hormone Resistance Syndrome
AbstractThyroid hormone resistance syndrome (RTH) is a rare disorder characterized by elevated levels of circulating free thyroid hormones, inappropriate TSH secretion, and reduced peripheral tissue responses to iodothyronine action. On the basis of clinical features, at least two different forms of RTH have been described: generalized resistance (GRTH) in which patients are asymptomatic with few clinical signs and pituitary resistance (PRTH) where patients present with some signs and symptoms associated with thyrotoxicosis. However, a review of the literature and our own experience indicates that there is a wide overlap of symptoms and signs exhibited by individuals with GRTH or PRTH. Assessments using biochemical and physiological indices of thyroid hormone action are useful, but limited by their lack of precision and also show an overlap between values recorded in GRTH and PRTH. In addition, we have observed significant temporal variations in clinical signs as well as in parameters of thyroid hormone action in the same individuals, with no correlation with their subjective symptoms. Recent genetic analyses indicate that patients with either GRTH or PRTH are heterozygous for mutations in the thyroid hormone receptor beta (TR beta) gene. Indeed, different clinical features have been observed in affected individuals within a kindred harboring the same Tr beta mutation, and identical mutations have been identified in unrelated kindreds classified as GRTH or PRTH. These data support the view that GRTH and PRTH are variable manifestations of a single genetic entity. Nevertheless, this clinical distinction will remain useful as a guide to the most appropriate treatment. The variable phenotypic spectrum of thyroid hormone resistance may be related to factors other than mutations in Tr beta that have yet to be elucidated.
Efficacy of Bromocriptine Administration for Selective Pituitary Resistance to Thyroid Hormone
AbstractThe relation between thyroid-stimulating hormone (TSH) and triiodothyronine (T3) was evaluated in a girl with the selective pituitary type of thyroid hormone resistance for more than 7 years to clarify whether bromocriptine was an effective treatment or not. Levels of T3 (before: 2.44 +/- 0.64 nmol/l, mean +/- SD) and TSH (4.81 +/- 2.52 mU/l) were significantly decreased during therapy (T3: 2.15 +/- 0.44 nmol/l; TSH: 1.59 +/- 0.78 mU/l). T3 x TSH, calculated as one of the indices of pituitary resistance, on bromocriptine therapy (3.229 +/- 1.255 mU/l x nmol/l) was significantly (p < 0.005) smaller than the product before the administration (11.298 +/- 5.891 mU/l x nmol/l). The results suggest that bromocriptine should be one of the agents initially considered for the treatment of pituitary resistance to thyroid hormone.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
