DeCure for Isolated thyroid-stimulating hormone deficiency
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for isolated thyroid-stimulating hormone deficiency — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleIsolated thyroid-stimulating hormone deficiency maps to a 5-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 isolated thyroid-stimulating hormone deficiency 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
phosphatase and tensin homolog (PTEN) — PTEN 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 +drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 1D5R · 2.1 Å · ligand L(+)-TARTARIC ACID (TLA). Experimental structure, not a prediction.
What the evidence adds up to
Levothyroxine is a commonly prescribed drug for thyroid disease, but the 1993 review addresses general hypothyroidism, not isolated TSH deficiency. In that review, replacement therapy aims to normalise serum TSH, and for most patients a full replacement dose is 1.6 micrograms per kilogram body weight, typically 75 to 100 micrograms per day for women and 100 to 150 micrograms per day for men. The review notes that excessive dosage may have adverse effects. No data in that paper concern isolated TSH deficiency.
A 2012 case report describes a 50-year-old woman admitted for a distal radius fracture who was incidentally found to have hypothyroidism with low serum free T4 and low TSH. After administration of exogenous TSH-releasing hormone, no TSH response was observed, while prolactin and other pituitary hormones responded appropriately. Pituitary MRI showed no abnormalities. The diagnosis was isolated TSH deficiency. This is the only abstract that directly addresses the disease. The report does not describe any treatment or outcome for this patient.
The remaining abstracts cover resistance to thyroid hormone, Graves' disease genetics, and PPARgamma resistance. A 2001 review of resistance to thyroid hormone describes patients with elevated thyroid hormones and failure to suppress pituitary TSH secretion, which is the opposite pattern to isolated TSH deficiency. A 2009 report of a patient with a truncated thyroid hormone receptor beta notes mild resistance to thyroid hormone with elevated free thyroid hormones and preserved responses to T3 administration. These conditions are distinct from isolated TSH deficiency and provide no treatment data for it.
What is still missing: any controlled trial or systematic treatment data for isolated TSH deficiency. The 2012 case report is a single observation with no intervention reported. There is no evidence on levothyroxine dosing, monitoring, or outcomes specific to this rare condition. Patient stratification by aetiology (pituitary versus hypothalamic) and prospective registry data would be needed before any treatment guidance could be considered.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Internal Medicine · 1993 · 336 citations
Levothyroxine Therapy in Patients with Thyroid Disease
AbstractPURPOSE: To review the indications for and the proper monitoring of levothyroxine therapy in patients with thyroid disease. DATA SOURCES: Relevant English language articles published from 1966 to 1992 were identified through a MEDLINE search and manual searches of both identified articles and selected endocrinology texts. STUDY SELECTION: Studies, case reports, and review articles that contained data on the pathophysiologic aspects of relevant thyroid disorders and on the pharmacologic aspects of, indications for, and administration of levothyroxine therapy. DATA EXTRACTION: Data on the epidemiology, clinical manifestations, complications, and treatment of thyroid disorders were analyzed with respect to patient selection, methods, diagnostic criteria, and conclusions. These data were used to develop a rational approach to the management of such patients. RESULTS OF DATA SYNTHESIS: Levothyroxine is a reliable and commonly prescribed drug to treat thyroid disease, but excessive dosage may have adverse effects. In patients with hypothyroidism, levothyroxine is used as replacement therapy. For most patients, therapy can be initiated with a full replacement dosage (1.6 micrograms/kg body weight), which is usually 75 to 100 micrograms/day for women and 100 to 150 micrograms/d for men. The goal is to normalize the serum thyroid-stimulating hormone concentration. Levothyroxine is also used to suppress the serum thyroid-stimulating hormone concentration. A trial of thyroid-stimulating hormone suppressive therapy is indicated for most patients with benign solitary nonfunctioning thyroid nodules and for those with a history of thyroid cancer. Levothyroxine in non-thyroid-stimulating hormone-suppressive doses may also be indicated for patients with nontoxic multinodular goiter and for certain patients after lobectomy for benign thyroid nodules. CONCLUSIONS: With proper patient monitoring, levothyroxine replacement therapy should be effective, inexpensive, and free of complications. Recommendations for thyroid-stimulating hormone suppression with levothyroxine are based on risk-benefit considerations of the biologic characteristics of the thyroid disorder and the individual patient.
Frontiers in Endocrinology · 2017 · 25 citations · open access
Genetics of Thyroid-Stimulating Hormone Receptor—Relevance for Autoimmune Thyroid Disease
AbstractProduction of thyroid-stimulating hormone receptor (TSHR) antibodies represents the hallmark of Graves' disease (GD) pathogenesis. Thus, for more than two decades the TSHR gene has been at the center of studies intended to elucidate its contribution to disease pathology. The advent of genome-wide association technology allowed to establish a strong association of the TSHR gene with GD. Subsequent fine-mapping studies narrowed the disease-susceptibility region to a 40 kb sequence in intron 1, where at least five GD-associated SNPs in tight linkage disequilibrium were identified. The current challenge is to understand the functional mechanisms by which these polymorphisms modify physiological processes and trigger disease. The aim of this review is to summarize the current knowledge on the role of the TSHR gene in GD pathogenesis, which has been gained through linkage and association studies, as well as to discuss the emerging mechanisms underlying biological implications of TSHR variants in the development of GD.
Biochemical Society Transactions · 2001 · 19 citations
Resistance to thyroid hormone, and peroxisome-proliferator-activated receptor γ resistance
AbstractResistance to thyroid hormone (RTH) is usually inherited in a dominant fashion, and is characterized by elevated serum thyroid hormone levels and failure to suppress pituitary secretion of thyroid-stimulating hormone, with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features suggesting predominant pituitary resistance (PRTH). In over 100 families with GRTH or PRTH, we have identified heterozygous mutations in the thyroid hormone receptor beta isoform (TRbeta), which localize to three regions (amino acids 234-282, 310-353 and 429-461) of the hormone-binding domain of the receptor. The mutant receptors are transcriptionally impaired, due either to reduced ligand binding or to attenuated interaction with co-activators, and inhibit wild-type TR action in a dominant-negative manner. In the TRbeta crystal structure, most RTH mutations cluster around the hormone-binding pocket, with receptor regions that mediate functions (DNA binding, dimerization, co-repressor recruitment) required for dominant-negative activity being devoid of natural mutations. The pathogenesis of variable tissue resistance is not fully understood, but may be related to the differing tissue distributions of TRalpha and TRbeta, and to variable dominant-negative activity of mutant receptors on different target genes. The nuclear receptor peroxisome-proliferator-activated receptor gamma (PPARgamma) regulates adipogenesis and mediates the action of thiazolidinediones - novel anti-diabetic agents which enhance tissue insulin sensitivity. The PPARgamma gene was screened in 85 subjects with severe insulin resistance, and two different heterozygous receptor mutations (P467L and V290M) were identified in three affected individuals. The PPARgamma mutants are markedly transcriptionally impaired due to altered ligand binding and co-activator recruitment. Analogous to RTH, they inhibit the function of wild-type PPARgamma when co-expressed, and such dominant-negative inhibition is linked to their ability to silence basal gene transcription via aberrant interaction with co-repressors. In addition to insulin resistance, all three affected subjects developed Type II diabetes mellitus and hypertension at an unusually early age. Our findings provide compelling evidence that PPARgamma is important in the control of insulin sensitivity, glucose homoeostasis and blood pressure in humans. Future studies aim to elucidate the mechanism by which this receptor regulates insulin action and vascular tone.
Mild resistance to thyroid hormone with a truncated thyroid hormone receptor ß
AbstractRecent studies have revealed mutations in the thyroid hormone receptor beta (TR beta) gene as a cause of the most cases of the thyroid hormone resistance syndrome. We have identified a novel nonsense mutation in codon 449 in the 3' end of exon 10 in the TR beta gene in a 16-year-old male patient with generalized resistance to thyroid hormone who also had familial thyroxine binding globulin deficiency. Receptor protein generated from this gene is thought to be 13 amino acid deficient at carboxy-terminus. Resistance to thyroid hormone was mild at least when the patient was evaluated. The patient was eumetabolic in the presence of elevated plasma-free thyroid hormone levels, and both thyrotrope and peripheral tissues responded to triiodothyronine (T3) administration. This mildness of resistance is in contrast to severe resistance to thyroid hormone in two previously reported cases with truncated receptors in which 16 amino acids or 11 amino acids were deficient at C-terminus. Thus, truncation of C-terminus of thyroid hormone receptor beta does not uniformly produce sever resistance.
AbstractLetters and Corrections1 January 1980Danazol and Thyroid FunctionROBERT L. BARBIERI, M.D.ROBERT L. BARBIERI, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-92-1-133_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In a recent issue Wortsman and associates (1) reported that women receiving 400 to 800 mg of danazol daily have a low thyroxine (T4) index and normal thyrotropin (TSH) levels. They concluded that some women receiving danazol might be hypothyroid. Their observations do not support their conclusion. Detailed analysis of the effects of danazol on thyroid function indices has shown that danazol lowers thyroxine-binding globulin (TBG) capacity, lowers total T4, and produces no change in free T4(hence the normal TSH) (2). One explanation of these thyroid function indices is that the androgenic effects of danazol result...References1. WORTSMANHIRSCHOWITZSOLER JJN. Danazol and thyroid function. Ann Intern Med. 1979;91:321. Letter. LinkGoogle Scholar2. PANNALLMAAS PD. Danazol and thyroid-function tests. Lancet. 1977;1:102. Letter. CrossrefMedlineGoogle Scholar1. TOFTSETHHUNTERIRVINE AJWW. Plasma thyrotrophin and serum thyroxine in patients becoming hypothyroid in the early months after iodine-131. Lancet. 1974;1:704-5. CrossrefMedlineGoogle Scholar2. FLEISHERMCCONAHEYPANKOW GWM. Serum creatine kinase, lactic dehydrogenase, and glutamic-oxalacetic transaminase in thyroid diseases and pregnancy. Mayo Clin Proc. 1965;40:300-11. MedlineGoogle Scholar3. SCARPALEZOSLYGIDAKISPAPAGEORGIOUMALIARAKOUKOULOMMATIKOUTRAS SCCSAD. Neural and muscular manifestations of hypothyroidism. Arch Neurol. 1973;29:140-4. CrossrefMedlineGoogle Scholar4. GOLDMANMATXMORTIMERFREEMAN JRRR. High elevations of creatine phosphokinase in hypothyroidism. JAMA. 1977;238:325-6. CrossrefMedlineGoogle Scholar5. HIRSCHOWITZSOLERWORTSMAN JNJ. Sex steroid levels during treatment of endometriosis. Obstet Gynecol. 1979;54:448-50. MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Peter Bent Brigham Hospital Boston, MA 02115 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByThe use of danazol as a treatment of endometriosisDanazol: Endocrine pharmacology and therapeutic applications 1 January 1980Volume 92, Issue 1Page: 133-134KeywordsGlobulinsThyroidThyroid-stimulating hormoneThyroxine Issue Published: 1 January 1980 PDF DownloadLoading ...
Soonchunhyang Medical Science · 2012 · 0 citations
A Case of Isolated Thyroid Stimilating Hormone Deficiency
AbstractIsolated thyroid stimulating hormone (TSH) deficiency is very rare. Only a few patients are reported in the world. A 50-year-old woman was admitted to Soonchunhyang University Cheonan Hospital because of a distal radius fracture. She was diagnosed with hypothyroidism incidentally. Serum free T4 and TSH were low. After administration of exogenous TSH releasing hormone, no TSH response was noted. The response of prolactin and other pituitary hormones were appropriate after stimulation. Pituitary magnetic resonance image did not reveal any abnormalities. The diagnosis of isolated TSH deficiency was established for this patient.
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.
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