TSH secreting tumors
- Are You Sure the Patient Has a TSHoma?
- What Else Could the Patient Have?
- Key Laboratory and Imaging Tests
- Other Tests That May Prove Helpful Diagnostically
- Management and Treatment of the Disease
What's the Evidence/References
Are You Sure the Patient Has a TSHoma?
Thyrotropin (TSH)-secreting pituitary adenomas (thyrotropinomas/TSHomas) are rare, accounting for only 2% of all secretory pituitary tumors, and <1% of all causes of hyperthyroidism. Thyrotropinomas are usually diagnosed in the fifth-sixth decades of life, and affects males and females equally. Despite the hallmark feature of central hyperthyroidism, thyrotropinomas often go undiagnosed for several years, or are inappropriately treated as primary hyperthyroidism.
The clinical presentation of a thyrotropin-secreting adenoma is dependent on two primary factors: the tumor's hormone secretory profile and its size. Most thyrotropinomas secrete TSH exclusively (~75%), and patients commonly present with symptoms of hyperthyroidism, including: fatigue, heat intolerance, irritability, anxiety, palpitations, insomnia, hair loss, increased sweating, diarrhea and irregular menses (in females). The symptomatology varies from mild to severe, and generally trends with the tumor size, although a small percentage of patients, particularly those with microadenomas (<1 cm), have clinically-silent disease. Defective TSH synthesis, and/or low levels of TSH secretion, likely account for this discrepancy.
In addition, concomitant growth hormone excess has been reported in ~15% of TSHomas, and patients may have a mixed clinical presentation of hyperthyroidism and acromegaly (or gigantism if pre-pubertal in onset). Potential symptoms of GH excess include: fatigue, headaches, hyperhidrosis, peripheral neuropathies, snoring, sexual dysfunction and arthralgias. Lastly, mixed thyrotropin and gonadotropin-secreting adenomas (usually clinically silent) have been rarely reported.
Pituitary TSH overproduction results in thyroid gland enlargement and hyperfunction. Goiter, including diffuse and multi-nodular, is a common sign (80-90%). Consistent with thyroid hormone overproduction, patients often present with signs of hyperthyroidism, albeit usually mild, including: weight loss, tachycardia, tremor, warm/moist skin, hyperkinesis and hyperreflexia. For tumors with concomitant prolactin hormone hypersecretion, patients may present with signs of hypogonadism, such as infertility and osteoporosis. In addition, premenopausal females may demonstrate galactorrhea, and males may demonstrate decreased body hair, anemia and gynecomastia (rarely).
In cases of TSH/GH tumor co-secretion, GH excess may dominate the clinical picture, and signs may include: acral changes (e.g., frontal bossing, prognathism and increased hands/feet size) and cardiovascular/metabolic changes (e.g., obstructive sleep apnea, hypertension, diastolic dysfunction, impaired glucose tolerance/diabetes and dyslipidemia).
Key Laboratory Findings
The hallmark of a thyrotropinoma is elevations of free circulating and total thyroxine (T4) and triiodothyronine (T3) levels, and a non-suppressed (inappropriately normal or frankly elevated) TSH level.
What Else Could the Patient Have?
Based on the rarity of thyrotropinomas (incidence of <3 case per million people per year), several other conditions characterized by high T4 and T3 levels, and/or a non-suppressed TSH level, should be considered in the differential diagnosis. These other conditions can be broadly grouped into four categories, and include:
Altered thyroid hormone binding proteins
Resistance to thyroid hormone (RTH)
Disorders of thyroid hormone transport, metabolism and displacement
Distinguishing a thyrotropinoma from these various conditions can often be established based on family history, clinical assessment, alternate thyroid function testing and pituitary imaging (
Differential Diagnosis of Euthyroid Hyperthyroxinemia
Ultrasensitive TSH assays have greatly improved the ability to detect thyrotropinomas, although methodological problems can occur. Most notably, the presence of human-anti-mouse antibodies (HAMA), or various heterophilic antibodies, such as rheumatoid factor, may falsely elevate TSH levels. Although relatively uncommon with most current assays (~5%), suspected cases of factitious TSH elevations can be excluded with either: 1) the use of a different TSH assay (i.e., chimeric human-animal antibodies with less susceptibility to this effect), 2) by the addition of animal blocking immunoglobulins, or 3) sample dilution, to disrupt interfering antibodies, and evidence of non-linear TSH measurement. Even rarer, methodological interferences can occur in patients with anti-T4 or anti-T3 auto-antibodies. In these cases, patients are clinically euthyroid and with normal TSH values, but with spuriously elevated total T4 and T3 values. Biochemically, these conditions can best be excluded by testing for free T4 and T3 levels, which are normal, and preferably by a two-step equilibrium dialysis method.
Altered Thyroid Hormone Binding Proteins
The vast majority of circulating thyroid hormone is protein-bound (T4-99.97%, T3-99.7%), so perturbations of binding proteins are a potential cause of altered total thyroid hormone levels. Most notably, qualitative and quantitative defects of thyroxine-binding globulins (TBG), transthyretin and albumin can occur. These potential abnormalities include inheritable defects (e.g., TBG excess and familial dysalbuminemic hyperthyroxinemia), or acquired conditions (e.g., hepatitis, pregnancy or various medications, such as oral estrogens, tamoxifen, raloxifene, morphine, mitotane, methadone, heroine and 5-fluorouracil) which increase TBG levels.
The binding protein abnormalities associated with TBG changes can be detected by a concomitant T3-resin uptake test (T3RU) which is low compared with the high total T4 and T3 levels (e.g., in true hyperthyroidism, T3RU and thyroid hormone level are both elevated). It is generally easier, however, to just test for free T4 and free T3 levels, which are normal. Of note, quantitation of T4 and T3 levels by liquid chromatography/tandem mass spectrometry may also be used in such situations, although this test is costlier and not routinely available.
Resistance to Thyroid Hormone (RTH) is a rare, autosomal-dominant disorder (1 in 40-50,000 live births) that is usually caused by mutations in the thyroid hormone receptor beta gene (THRB). These mutations cause varying degrees of tissue refractoriness to the actions of thyroid hormone. In the past, RTH was sub-categorized into generalized (GRTH), pituitary (PRTH) and peripheral tissue resistance (PTRTH) syndromes, although there is a significant overlap between these syndromes, and no established genetic basis for their differences.
RTH syndromes are congenital disorders, and patients are often diagnosed early in life, although mild RTH disease can go undiagnosed into adulthood. This makes distinguishing RTH from thyrotropinomas particularly challenging, since their clinical presentations are often similar (e.g., goiter and tachycardia), and both have biochemical evidence of central hyperthyroidism.
Disorders of thyroid hormone transport, metabolism and displacement, which may be confused with central hyperthyroidism, include:
The resolution phase of euthyroid sick syndrome/non-thyroidal illness, whereby TSH levels may be transiently elevated up to 20 uIU/ml, but with normal T4 and T3 levels.
Increased free T4 and T3 levels in patients on medications that displace thyroid hormone from TBG, such as heparin, high-dose lasix (>80 mg), nonsteroidal anti-inflammatory agents, phenytoin or aspirin.
Acute inhibition of T4 to T3 conversion, most notably from early amiodarone use (<3 months).
Partial selenocysteine enzyme mutations (i.e., selenocysteine insertion sequence binding protein 2 (SECISBP2) gene mutation). Results in a functional deiodinase deficiency.
Mild hyperthyroxinemia in patients with primary hypothyroidism and erratic/excessive TH ingestion relative to thyroid function testing.
Monocarboxylate transporter 8 (MCT8) mutations, an X-lined disorder of childhood-onset, of a defective thyroid hormone membrane transporter. Characterized by psychomotor retardation, hypotonia, spastic quadriplegia and additional neurological abnormalities. Demonstrates a characteristic pattern of normal TSH, low Free T4 and high FT3 levels.
Key Laboratory and Imaging Tests
Key Laboratory Tests for Thyrotropinomas
TSH levels are frankly elevated in ~70% of TSHoma patients, and are in the normative range in 30%. In general, the degree of TSH elevation does not correlate with T4 and T3 levels, and hyperthyroxinemia from 'normal' TSH levels is due primarily to tumor TSH secretion with increased bioactivity. Biochemically, thyrotropinomas and the thyroid hormone resistance syndrome are similar, although various basal and dynamic testing can be used to distinguish them.
Importantly, patients with untreated thyroid hormone resistance syndromes almost always have normal TSH values, compared to only 30% of TSHomas. Thyrotropinomas also frequently cause elevated alpha-glycoprotein subunit (GSU) expression and an elevated alpha-GSU/TSH molar ratio, presumably from excessive and unbalanced sub-unit formation, or the coexistence of an alpha-GSU and TSH-beta secreting tumors. The alpha/TSH molar ratio [defined as alpha subunit (in ng/mL), divided by TSH (in uIU/mL), and multiplied by 10], is normally less than unity. A ratio of >1.0 has been noted in ~75-80% of thyrotropinomas. Importantly, however, the utility of these diagnostic markers for thyrotropinoma detection are generally limited to macroadenomas and eugonadal patients. Specifically, post-menopausal women and men with primary hypogonadism frequently have elevated alpha-GSU levels and alpha-GSU/TSH molar ratios, which limits these markers in these patients.
Lastly, altered basal TSH secretion, specifically an absent diurnal TSH surge was reported in earlier studies of thyrotropinomas, although a more recent, larger study demonstrated a preserved, albeit delayed, TSH diurnal rhythm.
A further distinction between thyrotropinomas and RTH is based on the refractoriness of TSHomas to normal physiologic regulation, including thyroid hormone inhibition and thyrotropin-releasing hormone (TRH) stimulation. Of these regulators, the thyroid hormone suppression test has the best diagnostic performance. Specifically, a failed complete TSH suppression (i.e., an undetectable TSH level) after supraphysiologic exogenous thyroid hormone administration (T3 at 80-100 mcg/day divided in 3 administrations for 10 days, and sampling at 0, 5 and 10 days) has the highest sensitivity and specificity for thyrotropinomas (>90%).
Importantly, this test should not be performed in certain at-risk populations, including the elderly, patients with active coronary heart disease, or patients poorly tolerant of further T3 elevations.
Similarly, the TRH test has a high specificity for thyrotropinomas, with a blunted TSH response (defined as <2-fold increase in basal TSH levels after 200 microgram TRH administration and TSH sampling at 0, 20, 60, 90 and 120 minutes), observed in >80% of cases. Unfortunately, the utility of the TRH test is limited by its lack of availability in the U.S.
Imaging of Thyrotropinomas
A thin-cut, pituitary-dedicated magnetic resonance imaging (MRI), with and without gadolinium contrast, is the preferred modality to identify thyrotropinomas. This test allows for tumor characterization; its size and proximity to critical adjacent sellar structures, such as the cavernous sinuses and the optic nerve. A contrast-enhanced computed axial tomography (CT) scan is recommended for patients with contraindications to MRIs (e.g., pacemakers or corporal metal).
In contrast, patients with RTH syndrome do not have pituitary abnormalities. Importantly, the finding of a microadenoma in a patient with central hyperthyroidism, although suggestive of a TSH-secreting tumor, is not diagnostic, because of the high prevalence of incidental pituitary microadenomas in the general population (10-15%; mostly
In summary, diagnosing a thyrotropinoma, although challenging, can often be made based on a detailed history and physical exam, biochemical testing and radiologic evaluation. The recommended algorithm for navigating the potential etiologies of euthyroid hyperthyroxinemia is as shown in
Evaluation for the diagnosis of euthyroid hyperthyroxinemia
Other Tests That May Prove Helpful Diagnostically
Pathogenesis and Genetic Testing
The molecular mechanisms that cause thyrotropinomas are largely unknown. The vast majority of thyrotropinomas are monoclonally-derived, sporadic, benign tumors, and are only rarely associated with familial syndromes, such as multiple endocrine neoplasm, type I, or the familial isolated pituitary adenoma syndrome. Conversely, ~70% of patient with thyroid hormone resistance syndromes will have an inheritable mutation in the thyroid hormone receptor beta (THRB) gene, and analyses should be considered in patients with first-degree relatives with similarly abnormal thyroid function tests.
Other Peripheral Tissue Markers of Hyperthyroidism, such as the liver (with a low cholesterol and an elevated sex hormone-binding globulins) and bone (with an increased carboxyterminal cross-linked telopeptide of type I collagen) have been previously used to distinguish thyrotropinomas from THR, although these markers have sub-optimal test characteristics and are potentially influenced by other factors, such as age, medications and gonadal status. Similarly, inferior petrosal sinus sampling (IPSS), to detect a central-to-peripheral TSH gradient, before and after TRH stimulation, has been used to confirm TSH-secreting microadenomas, although the cut-off values have not been well-validated and TRH has limited availability.
Evaluation for Hormone Co-secretion and Mass Effects
Clinical and biochemical evidence of growth hormone and prolactin excess should be assessed in all patients with thyrotropinomas. In addition, hypopituitarism should be excluded in patients with macroadenomas. This entails basal pituitary hormone testing for the following:
Follicle stimulating hormone
A.m. testosterone (in men)
Estradiol (in women, and timed to the follicular phase of the menstrual cycle if possible)
Insulin-like growth factor (IGF-1)
Adrenocorticotropin hormone (ACTH)
Additional dynamic testing, such as insulin tolerance test or Cosyntropin stimulation test may be indicated for equivocal, basal cortisol results. In addition, if GH co-secretion is suspected and the screening IGF-1 level is equivocal, consideration could be given to an oral glucose tolerance test for growth hormone suppression. For patients with large pituitary tumors and subjective vision loss, particularly those with tumors that abut or distort the optic chiasm, on MRI, formal visual field testing should also be performed.
Additional Imaging Modalities
An Indium-111 octreotide scan, with single-photon emission tomography imaging, has been reported, in select cases, to identify TSH-secreting microadenomas or ectopic TSH tumors (e.g., nasopharynx), although this modality is rarely indicated.
The Problem of Previous Thyroid Gland Ablation
A significant percentage of thyrotropinoma patients (~30%) are mistakenly treated for Graves' disease, with radioiodine ablation or surgery. This not only delays the correct diagnosis, but often further elevates the TSH level, from a relative loss of T4 and T3 feedback inhibition, and also promotes tumor growth and invasiveness. Importantly, the basal and dynamic test characteristics for thyrotropinoma detection are similar in thyroid gland ablated patients, as untreated ones, although the former are less likely to have normal TSH values.
A Word of Warning
Patients with chronic and severe primary hypothyroidism can develop significant pituitary gland enlargement, from normal thyrotrope hyperplasia, which can be mistaken for a sellar/suprasellar tumor (pseudo-TSHoma) on MRI (
Thyrotrope hyperplasia (pseudo-TSHoma) before (left) and after (right) TH treatment x 3 months.
Management and Treatment of the Disease
Tumor-Directed Therapies for Thyrotropinomas
Tumor-directed therapies for thyrotropinomas include: surgical resection, medical treatment and radiation therapy. Frequently, a multi-modal approach is needed to control both tumor growth and hormone hypersecretion. In general, thyrotropinomas develop gradually and present non-emergently, except in the rare cases of pituitary apoplexy (i.e., pituitary hemorrhage or infarction associated with sudden headache, visual impairment, opthalmoplegia, and/or altered mental status).
Surgical resection, preferably by a transsphenoidal (TSS) approach, is the first-line therapy for most patients with thyrotropinomas, particularly at centers with neurosurgical expertise. Surgical cures, which are generally defined as gross-total tumor resection and the resolution of central hyperthyroidism, occur in upwards of 50-80% of cases, although cure is less likely for large and invasiveness tumors. Surgical debulking should always be considered in TSHoma patients, because of the potential benefits of:
Symptomatic relief from mass effects with macroadenomas
Preservation or restoration of normal pituitary gland function
An increased likelihood of subsequent medical or radiation therapy responses
Somatostatin analogs (SSA) are generally second-line therapy and are recommended for TSHoma patients who are not surgical candidates, or who are not cured surgically. In addition, somatostatin analogs are often used pre-operatively to normalize thyroid hormone levels and/or decrease TSHoma tumor size, although there are no studies demonstrating outcomes benefit.
Thyrotropinomas have a predominance of somatostatin receptor, sub-type 2 (SSTR2), and an overall excellent response to somatostatin analogs; both the short- and long-acting formulations.
For example, in an initial study of 73 thyrotropinoma patients given short-acting Octreotide, TSH and thyroid levels normalized in the vast majority of patients (>90%). Similar efficacies were demonstrated with slow-release formulations of somatostatin (e.g., Lanreotide SL-30 mg every 14 days) and monthly depot somatostatin formulations (i.e., Somatuline depot and Sandostatin LAR) and at standard doses. Monthly SSA formulations are recommended in the recent European guidelines for Thyrotropin-secreting pituitary adenomas diagnosis and management, based on their comparative convenience.
Once a monthly SSA is initiated, it should be titrated every 12 weeks (based on a trough free T4 level), and adjusted as needed, to maintain the free T4 level in the mid-normative range. Regarding tumor growth, somatostatin analogs stabilize the majority of thyrotropinomas, and cause significant tumor reduction in 40-50% of cases. Somatostatin analogues also have the advantage of effectively treating hyperthyroidism and mixed TSH/GH tumors, since GH tumors also frequently express SSTR2s (and SSTR5).
Somatostatin Side Effects
Abdominal cramping, bloating and mild steatorrhea often occur early in SSA treatment due to inhibition of pancreatic enzyme secretion, although these symptoms usually abate after the first few months. Somatostatin analogs can also cause impaired glucose tolerance (IGT), or less commonly frank diabetes from a transient inhibition of insulin release. Patients with pre-existing IGT/diabetes should be monitored for worsening blood sugar control, and managed accordingly.
Gallstones or gallbladder sludge develop in ~20-30% of patients on SSAs, but only 1%/year develop symptomatic cholecystitis. As such, patients should routinely be educated about the signs and symptoms of cholecystitis, but gallbladder ultrasound screening is not routinely warranted. Lastly, although long-term somatostatin treatment data is limited, it appears to be generally well tolerated (beyond the early GI side effects); <10% of patients develop drug tachyphylaxis or resistance.
Somatostatin Analog to Distinguish TSHomas from RTH
In equivocal cases of thyrotropinomas, for which a clear distinction from RTH cannot be made (e.g., <6 mm sellar tumors), consideration can be given to an empiric trial of somatostatin analogs therapy. Specifically a
Anti-Thyroid Hormone Medications
Although the long-term use of thyroid-directed therapies, before tumor-directed treatment, is associated with adverse effects on thyrotropinoma tumor growth, the short-term use of anti-thyroid medications is appropriate to render patients euthyroid before pituitary surgery, particularly when used in conjunction with somatostatin analogs. This is important in patients with moderate to severe hyperthyroidism to minimize the potential cardiovascular risks of atrial fibrillation and congestive heart failure.
Common anti-thyroid hormone regimens include methimazole (10-40 mg daily), or propylthiouracil (150-600 mg daily). In addition, beta-adrenergic blocking agents, such as atenolol (50-200 mg daily) or propranolol (40-160 mg daily) are often used for symptomatic relief of hyperthyroidism and cardiovascular stabilization.
Although most TSHoma express dopamine type 2 receptors, the use of bromocriptine and cabergoline is limited by incomplete tumor responses regarding TSH and thyroid hormone levels normalization and tumor shrinkage.
Radiation therapy is generally the third-line approach to TSHomas after inadequate surgical and medical responses. Although experience with radiation therapy in thyrotropinomas is far more limited than with other pituitary tumor sub-types, limited studies show excellent control of tumor growth with modern radiotherapy techniques. Conversely, hormone level normalization is often delayed by several months to years, similar to other secretory adenomas, and likely requires concomitant medical therapy during this latency period.
Definition of Cure and Recommended Follow-up
In patients not previously treated for hyperthyroidism, or rendered euthyroid long-term, the finding of a frankly suppressed TSH level, in the early post-operative period (i.e.,
Patients with presumed gross-total tumor resection, should be evaluated clinically (for signs and symptoms of hypo- or hyperthyroidism), biochemically (with basal pituitary and thyroid hormone levels), and radiographically (with pituitary-dedicated MRIs); initially at 3 months post-operatively and then annually for the first few years. No data on recurrence rates in TSHoma patients, deemed initially cured after surgery, have been reported, although is generally thought to be uncommon.
Conversely, patients with evidence of persistent or recurrent disease require more frequent monitoring, usually every 3-4 months, to assess subsequent treatment responses. Patients on somatostatin analogs should be monitored every 3 months, until there is evidence of disease control, and then less frequently thereafter (every 6-12 months). Patients who have undergone radiation therapy should be managed expectantly for hypopituitarism, by biannual pituitary hormone testing. Lastly, because of the risk of a secondary brain tumor after XRT (~2.0% at 20 yrs.), periodic pituitary MRI imaging, ~ every 5 years, is recommended.
What's the Evidence/References
The world literature on thyrotropinomas is limited to approximately 576 reported cases from 20+ studies. High-quality evidence from randomized, controlled studies is lacking. As detailed in the recently published 2013 European Thyroid Association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary adenomas, the highest quality of evidence exists for the diagnostic and management approaches detailed in this chapter. Conversely, only low-to-moderate qualities of evidence exists to support optimal peri-operative TSHoma management, assessment of cure and patient follow-up recommendations.
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**The original authors for this chapter were Drs. E. Chester Ridgway and Janice Kerr. The chapter was revised by Dr. Janice Kerr.
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