EndocrinologyTier 2Disease (DEADMAN)

Hypothalamic–pituitary axis disorders - thyrotropinoma (TSH-oma)

Description

TSH-secreting pituitary adenoma -> central (secondary) hyperthyroidism
The pattern: high fT4 and fT3 with a TSH that is normal or high - i.e. unsuppressed
- Normal feedback would drive TSH to <0.01
Rarest functioning pituitary tumour
~2/3 are plurihormonal - co-secrete GH (acromegaly) or prolactin most often

Before you call it a TSH-oma - exclude artefact and resistance

A single unsuppressed TSH with high free hormones is far more often an assay problem than a tumour.

<1-2% of all pituitary adenomas; ~1-2 per million population
M = F
Peak 5th-6th decade
Historically ~70-80% macroadenomas at diagnosis; proportion of microadenomas rising with earlier biochemical detection

Monoclonal thyrotroph adenoma
- Autonomous TSH secretion, partially resistant to T3/T4 negative feedback
- Secretes biologically hyperactive TSH (altered glycosylation) -> thyrotoxicosis at apparently modest TSH levels
Alpha-subunit is co-secreted in molar excess -> the diagnostic handle
Not associated with a single recurrent driver mutation; GNAS and menin mutations are rare
MEN1 and, rarely, McCune-Albright
Chronic untreated primary hypothyroidism -> thyrotroph hyperplasia that mimics an adenoma on MRI - it shrinks on thyroxine. Do not operate.

Step 1 - confirm the biochemistry is real

Repeat on a different assay platform
Heparin / LMWH (enoxaparin) artefact
- In vitro lipoprotein lipase release -> free fatty acids displace T4/T3 from binding proteins in the tube
- -> spuriously high free T4/T3 with a normal TSH - exactly the TSH-oma pattern
- Ask about heparin exposure, including line flushes, before any pituitary workup
Other interferences: biotin (high-dose supplements), anti-mouse/heterophile antibodies, anti-T4 autoantibodies, familial dysalbuminaemic hyperthyroxinaemia

Step 2 - TSH-oma vs resistance to thyroid hormone (RTH-beta)

Both give high fT4/fT3 with unsuppressed TSH.

	TSH-oma	RTH-beta

| Alpha-subunit:TSH molar ratio | >1 | normal |

| SHBG | high (peripheral thyrotoxicosis) | normal |

| TRH stimulation | blunted/absent TSH rise | normal/exaggerated rise |

| T3 suppression test | no suppression | partial suppression |

| Family history | absent | often positive (AD, THRB) |

| Pituitary MRI | mass | normal |

| Clinical | thyrotoxic +/- mass effect | often eu-/oligo-symptomatic, goitre, tachycardia |

Step 3 - localise and stage

MRI pituitary with contrast
Visual fields if macroadenoma
Full anterior pituitary screen - IGF-1, prolactin, cortisol, gonadotrophins
Alpha-subunit is less useful in postmenopausal women and men with hypogonadism (gonadotroph-derived alpha rises physiologically)

1. Surgery is first-line

Transsphenoidal resection - cure ~60-75% for microadenomas, lower for invasive macroadenomas
Pre-operative control of thyrotoxicosis with somatostatin analogue (octreotide/lanreotide) or antithyroid drug + beta blocker

2. Somatostatin analogues

Thyrotroph adenomas express SSTR2/SSTR5 -> normalise TSH and thyroid hormones in ~90%, shrink tumour in ~40-50%
Used pre-operatively, or as primary therapy when surgery is declined/unsuitable, or for residual disease

3. Radiotherapy

Conventional or stereotactic for residual/recurrent disease after surgery +/- medical therapy
Hypopituitarism is the expected late cost

What NOT to do

*Do not ablate or resect the thyroid.* Removing the target organ removes feedback -> TSH rises further, adenoma grows and becomes more aggressive
- This is the classic exam trap - prior thyroidectomy or RAI in a patient later found to have a TSH-oma
Antithyroid drugs alone have the same problem

Follow-up

Untreated -> thyrotoxicosis (AF, osteoporosis, cardiomyopathy) + progressive mass effect
Goitre in most (diffuse, from chronic TSH drive); nodules and, rarely, differentiated thyroid cancer
Cure defined as undetectable TSH with low fT4 post-operatively (transient central hypothyroidism is a good sign)
Recurrence ~10-20%, usually within 5 years -> long-term surveillance
Prognosis good for microadenomas; invasive macroadenomas may need multimodal therapy
Post-operative hypopituitarism, DI, CSF leak

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