CASE STUDIES

A Patient with Thyrotropinoma CosecretingGrowth Hormone and Follicle-Stimulating Hormone

with Low a-Glycoprotein: A New Subentity?

Tarik A. Elhadd,1 Sujoy Ghosh,1 Wei Leng Teoh,1 Katy Ann Trevethick,1 Zoltan Hanzely,2

Laurence T. Dunn,3 Iqbal A. Malik,1 and Andrew Collier1

Background: Thyrotropinomas are rare pituitary tumors. In 25 percent of cases there is autonomous secretion ofa second pituitary hormone, adding to the clinical complexity. We report a patient with thyrotropin (TSH)–dependant hyperthyroidism along with growth hormone (GH) and follicle-stimulating hormone (FSH) hyper-secretion but low a-glycoprotein (a-subunit) concentrations, a hitherto unique constellation of findings.Summary: A 67-year-old Scottish lady presented with longstanding ankle edema, paroxysmal atrial fibrillation,uncontrolled hypertension, fine tremors, warm peripheries, and agitation. Initial findings were a small goiter,elevated serum TSH of 7.37 mU=L (normal range, 0.30–6.0 mU=L), a free-thyroxine concentration of 34.9 pmol=L(normal range, 9.0–24.0 pmol=L), a flat TSH response to TSH-releasing hormone, and serum a-subunit of3.1 IU=L (normal, <3.0 IU=L). There was no evidence of an abnormal thyroid hormone b receptor by genotyping.Serum FSH was 56.8 U=L, but the luteinizing hormone (LH) was 23.6 U=L (postmenopausal FSH and LH referenceranges both >30 U=L) Basal insulin-like growth factor I was elevated to 487mg=L with the concomitant serum GHbeing 14.1 mU=L, and subsequent serum GH values 30 minutes after 75 g oral glucose being 19.1 mU=L and 150minutes later being 13.7 mU=L. An magnetic resonance imaging pituitary revealed a macroadenoma. Pituitaryadenomectomy was performed with the histology confirming a pituitary adenoma, and the immunohistochem-istry staining showed positive reactivity for FSH with scattered cells staining for GH and TSH. Staining for otheranterior pituitary hormones was negative. After pituitary surgery she became clinically and biochemically eu-thyroid, the serum IFG-1 became normal, but the pattern of serum FSH and LH did not change.Conclusion: This case of plurihormonal thyrotropinoma is unique in having hypersecretion of TSH, GH, and FSHwith low a-subunit. Such a combination may represent a new subentity of TSHomas.

Introduction

Thyrotropin (TSH)–secreting pituitary expansionmay be due to a pituitary adenoma (TSHoma) causing

secondary hyperthyroidism, or pituitary hyperplasia due tolongstanding untreated primary hypothyroidism (1,2).TSHoma is a rare disorder that accounts for 0.5–1% of allpituitary adenomas, can occur at any age, and has no sexpreference (1–4). Patients may present with a history of thy-roid dysfunction, often mistakenly diagnosed as Graves’disease, and can sometimes be incorrectly treated with sur-gery or radioactive iodine therapy. The diagnosis depends onthe demonstration of elevated free-thyroid hormones withnonsuppressed or elevated levels of TSH. The a-glycoprotein

subunit (a-subunit) values are usually elevated, and thea-subunit=TSH molar ratio is >1 in most cases (3,5,6). Absentor blunted TSH response to TSH-releasing hormone (TRH)stimulation is a typical finding. Pituitary imaging usuallydemonstrates a pituitary tumor, commonly a macroadenoma(3,5), but with the advent of ultra sensitive TSH assay morecases are being diagnosed relatively earlier as a micro-adenoma (7). Methodological interference of thyroid hormoneassay has to be excluded (8), and the rare condition of thyroidhormone resistance, which could well coexist with TSHoma,must also be excluded (9). Most TSH-secreting adenomas(72%) secrete TSH alone, (3), and in about 25% of cases,TSHoma have been shown to be plurihormonal. This iscommonly mixed growth hormone (GH)=TSHoma, followed

1Department of Medicine and Endocrinology, Diabetes Centre, Ayr Hospital, Ayr, United Kingdom.Department of 2Neuropathology and 3Neurosurgery, Southern General Hospital, Glasgow, United Kingdom.

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by prolactin (PRL)=TSHoma, and less so follicle-stimulatinghormone (FSH)=TSHoma (8). Hypersecretion of GH and PRLis the most frequent association resulting in acromegalyand=or amenorrhea or galactorrhea. Here we report an un-usual case of a TSHoma that was associated with GH and FSHhypersecretion, coupled with low a-subunit.

Case Report

A 67-year-old Scottish housewife was initially referredto Cardiology Clinic in our hospital with longstanding legedema, paroxysmal atrial fibrillation, and uncontrolled hy-pertension. She also suffered from osteoarthritis and dyslipi-demia. Her current medications were acetaminophen 500 mgtid, codeine phosphate 30 mg tid, simvastatin 10 mg qd, am-lodipine 10 mg qd, diclofenac 50 mg tid, indepamide 2.5 mgqd, bisoprolol 10 mg, and warfarin. Thyroid function testswere done to investigate the cause of her paroxysmal atrialfibrillation, and on finding raised thyroid hormone levels shewas referred to the Endocrine Clinic for further investigation.Here she was noted to have a small goiter and be clinicallythyrotoxic with fine tremors, warm peripheries, mild anxiety,and agitation. There were no features of thyroid-associatedophthalmopathy or thyroid acropachy. She did have a long-standing squint after an childhood accident.

Initial biochemical tests showed normal renal function,glucose, and electrolytes. Thyroid function tests showednormal free-triiodothyronine of 5.3 pmol=L (normal range,3.5–6.5 pmol=L), elevated free-thyroxine (fT4) of 34.9 pmol=L(normal range, 9.0–24.0 pmol=L), and elevated TSH of7.37 mU=L (normal range, 0.30–6.0 mU=L). Repeat TFTsshowed an fT4 of 41.8 pmol=L with detectable TSH of2.67 mU=L. The combination of elevated fT4 and elevated ornormal TSH in the context of clinical thyrotoxicosis raised thepossibility of TSHoma, assay interference, or alternatively

thyroid hormone resistance. Tests for thyroid hormone in-terference showed no abnormalities. She was started on car-bimazole 40 mg once daily. Subsequently magnetic resonanceimaging of the pituitary fossa revealed a pituitary macro-adenoma (1.5�1.3�1.1 cm) abutting the optic chiasma (Fig. 1).There was some extension into the right cavernous sinus.

Assessment of pituitary function was subsequently carriedout, which showed high FSH of 56.8 U=L (normal referencevalue >30 U=L for postmenopausal women), but low lutei-nizing hormone (LH) levels of 23.6 U=L (normal referencevalue >30 U=L for postmenopausal women). Repeat and ad-ditional studies showed an FSH of 67.3 U=L, LH of 26.3 U=L,PRL of 278 mU=L (normal range, 1–650 mU=L), and randomcortisol of 477 nmol=L (normal range, 280–700 nmol=L). Theinsulin-like growth factor I (IGF-1) was elevated at 487 mg=L(normal range, 30–260mg=L) and random GH was 19.1 mU=L.Combined dynamic pituitary function testing with TRH andLH-releasing hormone (LHRH) demonstrated a flat TSH re-sponse to 200 mg TRH and disparity between basal andstimulatory levels of LH and FSH (Table 1). On oral glucosetolerance test, GH levels showed a paradoxical rise (Table 2).The a-subunit only marginally elevated at 3.1 IU=L (normal,<3.0 IU=L), and the repeat value was low at 2.45 IU=L (Table1). The a-subunit=TSH molar ratio was <1.1. Serial a-subunitvalues during TRH stimulation were not available preopera-tively. Thyroid hormone receptor b genotyping was under-taken by sequencing the exons encoding the hormone-bindingdomain of the thyroid hormone receptor b gene. No abnor-

FIG. 1. Magnetic resonance imaging scan of the pituitaryshowing a pituitary macroadenoma (1.5�1.3�1.1 cm) abut-ting the optic chiasm.

Table 1. Combined Thyrotropin-Releasing Hormone

and Lutenizing Hormone–Releasing Hormone

Stimulation Tests

Basal 20 min 60 min

Preop TRH TSH mU=La 5.79 5.72 5.67a-Subunit (IU=L)b 2.5 & 3.1

Postop TRH TSH 1.31 2.59 2.36a-Subunit 0.65 1.10 0.95

Preop LHRH LH U=Lc 10.7 42.1 47.3FSH U=Lc 55 77 86

Postop LHRH LH 16 34 37FSH 57 74 70

aTSH normal reference range is 0.3–5.4 mU=L.ba-Subunit normal reference value is <3.0.cFSH=LH normal reference value for postmenopausal women is

>30 U=L.TSH, thyrotropin; TRH, TSH-releasing hormone; LH, luteinizing

hormone; LHRH, LH-releasing hormone; FSH, follicle-stimulatinghormone.

Table 2. Growth Hormone Response

to 75 g Oral Glucose Tolerance Test

Basal 30 60 90 120 150 180 240

Preop GHmU=La

14.1 19.1 11.2 8.9 11.8 11.9 13.7

IGF-1mg=Lb

487

Postop GH 0.42 0.12 0.20 2.31 4.96 6.98 7.86IGF-1 101

aGH normal reference value is <10.0 mU=L.bIGF-1 normal reference range is 30–260mg=L.GH, growth hormone; IGF-1, insulin-like growth factor I.

900 ELHADD ET AL.

malities were detected. This, taken with the flat TSH responseto TRH stimulation, confirmed that she did not have thyroidhormone resistance. Ultrasound of the neck showed evidenceof multinodular goiter with several small focal nodulesthroughout each lobe with the largest measuring approxi-mately 8 mm. Assessment of visual fields did not show anydefect.

Treatment options were discussed with the patient. Shewas reluctant to have pituitary surgery. She agreed to a trial ofoctreotide but could not tolerate it. After a few injections shedeveloped intense nausea and abdominal pain. Octreotidetreatment was stopped and carbimazole was increased to50 mg daily as her fT4 remained elevated (36 pmol=L). Shethen agreed to have transsphenoidal pituitary adeno-mectomy. The operation was uneventful and the patientmade excellent recovery. The histology showed a pituitarytumor composed of moderately pleomorphic epithelioid cellsarranged in a trabecular pattern surrounded by hyalinizedblood vessels. Mitotic figures were inconspicuous; Ki67

activity was below 3% (Fig. 2). The immunohistochemistryfor various anterior pituitary hormones, using antihumanmouse IgG=kappa antibodies (Bio-Genex; Emergo Europe,The Hague, The Netherlands) showed diffuse immune reac-tivity to FSH, while scattered cells were immune reactive toTSH and GH. Immunocytochemistry staining for LH, adre-nocorticotropic hormone, and PRL was negative (Figs. 3–5).

The patient became biochemically and clinically euthy-roid after surgery. Her TSH declined to 1.39 mU=L, the free-triiodothyronine to 1.3 pmol=L, and the fT4 to 12.2 pmol=L,and these values remained in the normal range for severalweeks after carbimazole was discontinued. Repeat thyroidand basal pituitary hormones 3 months after surgery werenormal. Combined dynamic pituitary function tests done4 months after operation showed near normalization of herTSH response to TRH stimulation and normal a-subunit re-sponse to TRH stimulation (Table 1). However, the disparitybetween basal FSH and LH persisted. The LHRH-stimulatedLH response was adequate, but the FSH response was stillabnormal (Table 1). The fT4 at this time was also normal at

FIG. 2. Hematoxylin & eosin stain of the pituitary tumor(�400) showing moderately pleomorphic epithelioid cellsarranged in a trabecular pattern.

FIG. 4. Immunohistochemical staining of the thyrotropin-producing cells (�400) among the tumor cells.

FIG. 3. Immunohistochemical staining of the follicle-stimulating hormone producing cells (�400) among thetumor cells.

FIG. 5. Immunohistochemical staining of the growthhormone–producing cells (�400) among the tumor cells.

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17 pmol=L. Oral glucose tolerance test using 75 g of anhydrousglucose showed suppression of GH, and circulating IGF-1was normal (Table 2). Assessment of adrenocortical functionusing 250 mcg of cosyntropin revealed a satisfactory cortisolresponse with 0, 30, and 60 minute values of being 465, 684,and 738 nmol=L, respectively. Repeat magnetic resonanceimaging pituitary 6 months after surgery showed changesconsistent with removal of the previous adenoma and nosigns of tumor recurrence. The patient remained symptomfree with normal thyroid function for more than 10 monthsafter pituitary surgery.

Discussion

The prevalence of thyrotroph adenomas has increased overthe last decade with the introduction of ultra sensitive TSHimmunoassays as well as free-thyroid hormone assays thatare no longer obscured by abnormal serum transport proteins(1). Plurihormonal thyrotropinomas have been reported(10,11), but such tumors, like the one in our patient, behavedlike true TSHomas (8). To our knowledge, a mixed TSHomawith hypersecretion of both FSH and GH and low a-subunithas not been reported. Patrick et al. (1994) reported a manwith longstanding thyrotoxicosis who had elevated circulat-ing TSH and FSH. His pituitary tumor stained for TSH, FSH,and GH (12). He had no clinical signs of GH hypersecre-tion (12). A low a-subunit in TSH producing tumors hasrarely been reported (8,13). Terzolo et al. (1991) reported aTSH microadenoma composed of two types of cells, one se-creting a-subunit and TSH and the other secreting only thea-subunit (14).

In a large series from the NIH, the most specific test for aTSHoma was a flat or decreased response to TRH, followedby an elevated a-subunit, elevated baseline TSH, and elevateda-subunit=TSH ratio (5). Absolute values of a-subunit havegood sensitivity and specificity for pituitary tumors but can bemisleading if used alone (6). It is surprising that our patient’sa-subunit was low in the face of her high serum FSH andabundance of FSH-producing cells. This adds to the veryunusual aspects of her pituitary disorder.

It is intriguing that, despite the paucity of thyrotrophs onimmunohistochemical staining, our patient’s features werethat of a true TSHoma. She had both clinical and biochemicalthyrotoxicosis that was successfully treated with tumor re-section, confirming the TSH-dependent nature of her hyper-thyroidism. Autonomous GH secretion was also present bybiochemical testing despite a paucity of clinical findings. Theclinical features of acromegaly are known to take some time toevolve and may appear many years of the onset of biochem-ical GH hypersecretion. The IGF test is consistent with thepatients GH being biologically activity. The elevated FSHcoupled with inappropriately low LH for her postmenopausalstate indicates abnormal gonadotrophin secretory dynamics.Finally, there was predominant FSH staining in the tumor. Allof these factors support the notion that she had autonomousFSH secretion. As she was postmenopausal the FSH hyper-secretion was of no biological significance (15,16). Staining ofFSH in mixed thyrotropinomas has been reported (17,18), butabsence of a-subunit hypersecretion and evidence for auton-omous GH secretion in our patient makes her case unique.

The pathogenesis of this patient’s pituitary disease is un-clear. We do not have molecular or genetic data to give insight

into the plurihormonal character of her adenoma. Pit-1, thepituitary-specific transcriptional factor, is a nuclear factor thatis known to regulate the expression of GH, PRL, and TSHgenes (19–21). The Pit-1 gene has been shown by Sanno et al.(2001) to be expressed in TSHomas by both immunohisto-chemistry and in situ hybridization (11). Gsp oncogene, whichoccurs in 30–40% of GH secreting adenoma, has not beenreported in TSHomas, and mutations of other oncogeneslike ras and protein kinase C have not been studied inTSHomas (1,3). Tumor suppression genes involving p53 mu-tations have been limitedly studied in TSHoma, and it hasbeen negative (1,3).

In conclusion, we postulate that our patient may representa hitherto unrecognized subentity. If younger patients were todevelop a similar problem, they might have clinical signs re-lating to GH and FSH hypersecretion in addition to thyro-toxicosis. Importantly, this case also highlights the fact thatelevated serum a-subunit concentrations are not invariablypresent in functioning TSH producing pituitary tumors.

Acknowledgments

The authors would like to thank the nurses and ward staffof station 14 at Ayr Hospital, Scotland. We would also like tothank Dr. Brian Kennon of the Southern General Hospital,Glasgow, for providing the medical care for the patient duringher operation in Glasgow, and Prof. Krishna Chatterjee andDr. David Halsall, Departments of Medicine and Biochem-istry, Addenbrooke Hospital, Cambridge, United Kingdom,for helping out with the tests for thyroid hormone resistance.

Disclosure Statement

The authors have no conflict of interest to declare.

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Address correspondence to:Tarik A. Elhadd, M.D., FRCP

Department of Medicine and EndocrinologyDiabetes Centre, Ayr Hospital

Dalmellington RoadAyr KA6 6DX

ScotlandUnited Kingdom

E-mail: tarikelhadd58@gmail.com

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