Thyrotropin alfa

Thyrotropin alfa is recombinant human TSH produced in CHO cells, consisting of a 92-residue alpha subunit shared with LH, FSH and hCG and a 118-residue TSH-specific beta subunit, both glycosylated, giving a mass in the region of 28 to 30 kDa. It binds the Gs-coupled TSH receptor on thyroid follicular cells and any differentiated thyroid cancer that retains it, upregulating the sodium-iodide symporter and thyroglobulin synthesis and secretion. That is what makes it useful: administering it lets clinicians perform radioiodine imaging, radioiodine ablation and stimulated thyroglobulin measurement while the patient stays on levothyroxine, avoiding the weeks of profound hypothyroidism that the withdrawal alternative requires.

Targets: TSH receptor, Sodium-iodide symporter, Thyroglobulin secretion

• · 0.9 mg per dose, two doses total. The regimen is fixed and not titrated.

Work out your exact syringe units →

• very commonNausea— The most frequently reported effect, usually within 24 hours of injection.
• commonHeadache
• commonFatigue, dizziness and flu-like symptoms
• uncommonTransient swelling and pain in residual thyroid or metastatic tissue— Clinically important where metastases are in the brain, spine or airway, because swelling in a confined space can cause acute neurological compromise. Pre-treatment with corticosteroids is standard in that situation.
• rareTransient hyperthyroidism— In patients with substantial remaining functional thyroid tissue.

• Hypersensitivity to bovine or human TSH
• Caution when metastases sit where local swelling would be dangerous, such as CNS or airway
• Reduced renal function slows clearance and prolongs TSH elevation

• redundantcosyntropin — Both are pituitary-hormone diagnostics, but for entirely different axes; listed only because they are often confused as a category.

• · Stimulated serum thyroglobulin and anti-thyroglobulin antibodies at 72 hours
• · Neurological status where metastases are in critical locations
• · TSH level if the response is being verified

Prescription drug in the US and EU, used almost exclusively in specialist thyroid cancer care.

• Thyrogen FDA prescribing information (label)
• Haugen et al. 1999 JCEM, comparison of recombinant human TSH and thyroid hormone withdrawal for thyroid cancer surveillance (trial)
• American Thyroid Association guidelines for differentiated thyroid cancer (guideline)

The TSH receptor is a class A GPCR with a large leucine-rich extracellular domain, expressed on thyroid follicular cells and retained by most well-differentiated thyroid cancers. Gs coupling raises cyclic AMP and drives the two things this drug exists to produce: transcriptional upregulation of the sodium-iodide symporter, which pulls radioiodine into the cell, and upregulation of thyroglobulin synthesis and secretion, which makes serum thyroglobulin a usable tumour marker. At higher occupancy the receptor also recruits Gq, adding phospholipase C signalling, and that is thought to contribute to the acute swelling of thyroid tissue that occasionally causes trouble. The clinical problem this solves is worth stating plainly, because it is easy to forget how bad the alternative was. To get a TSH-stimulated thyroglobulin or an effective radioiodine uptake you need TSH above about 30 mU/L. The traditional route was to stop levothyroxine for three to six weeks and let the patient become profoundly hypothyroid, which meant fatigue, cognitive slowing, depression, inability to work or drive safely, and a period of accelerated tumour growth in an unsuppressed state. Thyrotropin alfa produces a higher and more predictable TSH peak than withdrawal does, in two injections, with the patient euthyroid throughout. That is the whole value proposition, and the randomised data showed equivalent diagnostic and ablative outcomes.

Timing errors ruin the test. The two injections are 24 hours apart, radioiodine goes in 24 hours after the second, the scan is 48 hours after the radioiodine and the thyroglobulin is drawn at 72 hours after the second injection, and a protocol that drifts by a day produces an uninterpretable result. Second, measuring thyroglobulin without simultaneously measuring anti-thyroglobulin antibodies: in the quarter of patients who have them, the thyroglobulin will read falsely low and a recurrence gets missed. Third, iodine contamination from contrast or amiodarone. Fourth, giving it to a patient with significant residual functioning thyroid tissue, who can develop transient hyperthyroidism. Fifth, forgetting the swelling risk in critical locations, which is rare but is the one way this benign-seeming diagnostic can cause serious harm. Sixth, reconstituting with bacteriostatic rather than sterile water, or shaking the vial, both of which risk the protein.

1. 900 mcgDay 1 — 0.9 mg intramuscularly into the buttock. Reconstitute the 1.1 mg vial with 1.2 mL of sterile water for injection to give 0.9 mg per mL, swirl gently, do not shake. Bacteriostatic water is not the labelled diluent.
2. 900 mcgDay 2 — Second 0.9 mg intramuscular dose exactly 24 hours after the first. The regimen is fixed and is never titrated.
3. —Day 3 — Radioiodine is administered 24 hours after the second injection. Scanning is performed 48 hours after the radioiodine.
4. —Day 5 — Serum thyroglobulin and anti-thyroglobulin antibodies drawn 72 hours after the second injection.

• TSH receptor on thyroid follicular cells and differentiated thyroid carcinoma — High; recombinant human TSH is identical in sequence to the endogenous ligand. Numeric affinity not resolved this session.

  Gs-cyclic AMP signalling upregulating the sodium-iodide symporter and thyroglobulin synthesis and secretion, making radioiodine uptake and stimulated thyroglobulin measurement possible on levothyroxine.

• Sodium-iodide symporter (NIS) expression

  Transcriptional upregulation, which is the mechanism that allows both diagnostic scanning and therapeutic ablation.

• TSH receptor on residual and metastatic tumour tissue — High where the receptor is retained

  The same stimulation causes transient swelling, which is clinically dangerous when metastases sit in the brain, spinal canal or airway. Corticosteroid pre-treatment is standard in that situation.

• Haugen 1999 comparison of recombinant human thyrotropin and thyroid hormone withdrawal Randomised comparative trial · n=229 · 1999

  Concordance of radioiodine whole-body scans between recombinant TSH stimulation and thyroid hormone withdrawal in patients with differentiated thyroid cancer. Scans were concordant in 195 of 220 patients, 89 percent. Combining radioiodine imaging with stimulated thyroglobulin detected thyroid tissue or cancer in 93 percent of patients with localised disease and 100 percent with metastatic disease, establishing rhTSH as a safe and effective alternative to withdrawal.

Serum TSH peaks at a median of 10 hours after each injection, with a range of 3 to 24 hours, and the elimination half-life of about 25 hours means the two doses build to a sustained elevation across roughly three days. Nausea, the most common adverse effect, usually appears within 24 hours of an injection and settles quickly. The whole protocol from first injection to thyroglobulin result spans about five days.

The important pairing is with corticosteroids: where metastases sit in the brain, spinal canal or airway, TSH-driven swelling in a confined space can cause acute neurological compromise, and pre-treatment with glucocorticoids is standard. The other essential co-management is the low-iodine diet before radioiodine, since dietary iodine competes at the sodium-iodide symporter and will blunt uptake regardless of how good the TSH stimulation was. Amiodarone and iodinated contrast are hard stops: both flood the iodine pool and can make radioiodine therapy useless for months, and a recent CT with contrast is a common and avoidable reason a scan is wasted. Levothyroxine continues unchanged throughout, which is the entire point of the drug.

Against thyroid hormone withdrawal: equivalent diagnostic and ablative outcomes with none of the three to six weeks of profound hypothyroidism, and a more predictable TSH peak. Withdrawal remains the fallback where thyrotropin alfa is unavailable or unaffordable, and it may still be preferred in some high-risk therapeutic settings where maximal and prolonged TSH stimulation is wanted. Against unstimulated thyroglobulin on a sensitive modern assay: this is the real modern question, because high-sensitivity thyroglobulin assays combined with neck ultrasound now detect most recurrences without any stimulation at all, and current guidelines use stimulated thyroglobulin far more selectively than they did in 1999. Against cosyntropin: they get grouped together as pituitary-hormone diagnostics but they interrogate entirely different axes and the comparison is a category error.

Not a monthly drug. Thyrogen is priced per two-vial course and has historically been expensive, with the cost frequently weighed against the alternative of several weeks of a patient being unable to work. I did not source a figure this session.

• ?Volume of distribution, clearance and protein binding are all uncharacterised in the label.
• ?The Haugen trial's duration is not applicable in weeks, so durationWeeks is null; 229 patients were enrolled and 220 completed both scan phases.
• ?No numeric TSH receptor binding affinity was resolved this session.
• ?The molecular weight is described in the region of 28 to 30 kDa in the Core record but I did not resolve a label figure this session.
• ?No cost figures were sourced.

• A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer Haugen BR, et al., Journal of Clinical Endocrinology and Metabolism, 1999 · PMID 10566623

  The pivotal comparison that made hypothyroid withdrawal optional rather than mandatory for thyroid cancer surveillance.

• THYROGEN (thyrotropin alfa) for injection - FDA prescribing information Genzyme Corporation, DailyMed

  Source of the 116 plus or minus 38 mU/L peak TSH, the 3 to 24 hour range with a 10 hour median, the 25 plus or minus 10 hour elimination half-life, and the 92-residue alpha and 118-residue beta subunit composition with sialylation but no sulfation.