TSH-OMA

Pascual De Santis

Endocrinology Grand Rounds

April 6, 2006

History of Present Illness

• LB is a 81 y/o WM who was diagnosed with a TSH producing adenoma in May of 2004.

• During the endocrine w/u at SLU the tumor was found to co-secrete GH.

• The patient was on treatment with octreotide and pegvisomant, but his insurance refused to pay for the pegvisomant. Therefore, he presented to the VA seeking a second opinion and financial assistance for his treatment.

Past Medical/Sx History• Anemia, initially found in the 60s. Current w/u at the VA

revealed chronic disease anemia + hemoglobinopathy that responds to erythropoietin

• 1968 Nephrolithiasis surgery• 12/94 Bladder tumor s/p bladder cauterization.• 9/96 Swelling of the ankles• 6/02 CHF/Afib, and elevated TSH • 9/2002 Hydrocele removal• 2/04 Frank hyperthyroid symptoms with TSH• 5/04 Pituitary tumor dx as an incidental finding• Goiter noticed on 5/03 R. hemythyroidectomy on 9/05 due to

evidence of compression on CT.

• HTN-long standing

• DM newly diagnosed around the time of diagnosis of the pituitary tumor

• OA

• Hearing loss

Past Medical/Sx History

Family History

• Father: Lung CA, HTN, died at 69 from CVA

• Mother: died at 66 from complications during gallbladder surgery.

• Brother: alive 73-Prostate Ca.

• Brother: died at 82 with Alzheimer’s

• Brother: died at 72 from Lung Ca.

• Niece and her son on thyroid hormone

• Negative for endocrine tumors or nephrolithiasis

Social History

• Married for 55 years

• Denies ETOH, Tobacco or drugs

• Retired.

Allergies• PCN: rash

Medications• Sandostatin LAR 10 mg

IM 1X/month• Pegvisomant 10 mg SQ

1X/day (off x 3 w)• Methimazole 5 mg BID• Prednisone 5 mg QD• Glipizide 2.5 mg QD• Warfarin 4/2 mg• Carvedilol 25 mg BID• Furosemide 20 mg QD• Digoxin 0.125 mg QD• Lisinopril 40 mg QD

• Loratadine 10 mg QD

• Ranitidine 150 mg QD

• Celebrex 200 mg QD PRN

• Procrit 10,000 U 1X/week

• Metoclopramide PRN

• Ultracet PRN

• Vit E

• Calcium + Vit D

• Folic Acid

• Glucosamine

ROS

• Fatigue, Dyspnea on moderate exertion.

• LBP and general joint pain that improved on Pegvisomant.

• Denies palpitations, CP, PND, orthopnea

• Denies, diaphoresis, diarrhea, constipation, weight or appetite changes.

• Denies H/A, visual changes, changes in shoe, ring or hat size.

• Denies major changes in his facial features

Physical Examination • BP: 166/65, HR: 69, RR: 16, T: 97.5, WT: 169 Lb• General: Appears frail but not in acute distress.• HEENT: Normal visual fields by confrontation. Wide nose

base and protuberant lower lip. No evidence of prognathism. No lid lag or exophthalmos

• Neck: supple, no JVD, large left thyroid lobe.• CV: irregularly irregular and bradycardic HS.• Lungs: CTA bilaterally• Abdomen: no HSM• Extremities: No edema• Skin: Normal thickness, no skin tags• Musculoskeletal: Normal muscle strength bilaterally, no major

joint deformities appreciated• Neuro: AOX3, nonfocal, DTR NL, no distal tremor

Laboratory Data on 5/18/2004• TSH: 27.13 (0.4 – 5.5)• FT4: 6.9 (0.8 – 2.7)• FT3: 1124 (230 – 420)• SHBG: 79 (7 – 50) sub-unit: 42.8 ( 1)• GH: 10.5 (0 – 10)• IGF1: 567 (71 – 290)• LH: 2 (2 – 36)• FSH: 1.6 ( 0 – 87)• Total Test: 77 (241 – 827)• Free Test: 14 (34 – 194)

• ACTH: 20 (0 – 70)

• Cortisol: 17 (4 –22)

• ADH: 2.6 (1 – 13.3)

• DHEA-S: 63 (10 – 285)

• Calcium: 9.7

• Albumin: 3.8

• Electrolytes: Normal

• Glucose: 131

• Creatinine: 1.0

• TPO Ab: 41 (0 – 2)

Pituitary MRI

Concepts and Historical Notes• “TSH-secreting Pituitary Tumors” includes two opposite

clinical conditions: True neoplasia resulting in central Hyperthyroidism “TSH-oma”, and Pituitary hyperplasia resulting from long standing hypothyroidism.

• Syndromes of “Inappropriate secretion of TSH” (IST) include the Syndrome of “Resistance to Thyroid Hormone” (RTH) and TSH-omas.

• The first case of TSH-oma was documented in 1960 “Remission of Grave’s disease following radiotherapy of pituitary neoplasm”

Reported TSH-oma Series

• Beck-Peccoz et al. 1996 Thyrotropin-Secreting Pituitary Tumors., Endocrine Rev. 17:610 – 638. Reviewed and analyzed 280 cases reported up to January 1996

• Brucker-Davis et al. 1999 JCEM 84: 476 – 486. NIH series of 25 patients

• Valdes-Socin et al. 2003 European Journal of Endocrinology 148: 433 – 442. 43 patients from 6 Belgian and French centers

Occurrence

•Represents 1% of Pituitary adenomas

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Pathogenesis

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Pathogenesis

• Decreased expression of TR in 2 TSH-omas. Gittoes et al 1998 Thyroid 8:9-14

• Somatic mutation of the TR in 1 patient at the NIH. Ando et all 2001 JCEM 86(11)5572 – 5576.

• Aberrant alternative splicing of THR in 1 patient at the NIH. Ando et all 2001 Molecular Endocrinology 15(9):1529-1538

• Loss of heterozygosity at the SS receptor type 5 locus in 1 patient. Filopanti et al., 2004 J. Endocrinol. Invest. 27: 937-942.

Secretion Pattern

Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Valdes Socin et al. 2003 European Journal of Endocrinology 148: 433 – 442.

Clinical Findings

• 1/3 of pts present with previous thyroid intervention

• They can occur at any age (11 – 84 y)

• No preferential incidence in females

• Clinical features of hyperthyroidism are progressive and often milder than expected

• Goiter is present in 94%

• 90 % are macroadenomas

Clinical Findings

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Clinical Findings

•Brucker-Davis et al. 1999 JCEM 84: 476 – 486.

Baseline Laboratory Findings

• Non-suppressed TSH + high free thyroid hormones.

-1/3 of patients without previous thyroid intervention had normal TSH.

-1/10 of patients with previous thyroid intervention had normal TSH

• Elevation of free -subunit, as well as -subunit/TSH molar ratio

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Baseline Laboratory Findings• Elevation of free -subunit. - < 3 g/L in males and pre-menopausal women - < 5 g/L in post-menopausal women

• Maximal values for controls: - Normal TSH, FSH and LH: 1.1 g/L - Normal TSH, FSH and LH: 4.2 g/L - TSH and normal FSH and LH: 5 g/L - TSH, FSH and LH: 6.2 g/L

•Brucker-Davis et al. 1999 JCEM 84: 476 – 486.

•Beck-Peccoz et al. 1992 Trends Endocrinol Metab 3:41-45

Baseline Laboratory Findings

-subunit/TSH molar ratio maximal values for controls

- Normal TSH, FSH and LH: 5.7

- Normal TSH, FSH and LH: 29.1

- TSH and normal FSH and LH: 0.7

- TSH, FSH and LH: 1.0

•Beck-Peccoz et al. 1992 Trends Endocrinol Metab 3:41-45

Baseline Laboratory Findings

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Parameters of Peripheral Thyroid Hormone Action

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Dynamic Testing

TRH stim test T3 suppression test

•Normal 200%

•Decreased 120-200%

•Flat 120 %

Dynamic Testing

•Brucker-Davis et al. 1999 JCEM 84: 476 – 486.

Assessment of Diagnostic Tests

•For patients with intact thyroid the best combined sensitivity and specificity was seen with the TRH test and the -subunit measurement.

•For patients with previous thyroid treatment the best combined sensitivity and specificity was seen with -subunit and the -subunit/TSH ratio

•Brucker-Davis et al. 1999 JCEM 84: 476 – 486.

Differential Diagnosis

Diagnosis

Differential Diagnosis

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Octreotide Test• Short course of 100 g TID x 72 h. vs LAR 30 mg

Q month x 2

Mannavola et al. 2005 Clinical Endocrinology 62,176-181

Treatment and Outcome

Valdes Socin et al. 2003 European Journal of Endocrinology 148: 433 – 442.

52.7 %•2 pt wating for sx

•2 pts declined sx

•1 pt not surgical candidate

•2 pt without visible adenoma

Criteria for Cure

• Euthyroidism and absence of visible tumor on imaging is not enough.

• Undetectable TSH 1 – 7 days after SX.

• T3 suppression test.

• Normalization of -subunit and/or -subunit /TSH molar ratio.

Losa et. al JCEM 1996, 81(8):3084-3090

Medical TherapyShort-acting Octreotide

• In 73 cases, Octreotide (50 – 750 g BID or TID) was effective in reducing TSH and -subunit around 90 % of the cases

• Normalization of TSH in 79 % of cases.• Only in 4 % of the cases, true resistance to

increasing doses of Octreotide • Shrinkage of tumor detected in 52 % of cases• Vision improvement in 75 % of cases

•Beck-Peccoz et al. 1996 Endocrine Rev. 17:610 – 638.

Medical TherapyOCT-LAR

Caron et al. 2001 JCEM 86(6):2849-2853

Medical TherapyOCT-LAR

Caron et al. 2001 JCEM 86(6):2849-2853

0

10

20

30

40

50

60

70

80

01002003004005006007008009001000

PTU 200 TID

Sandostatin 150 mcg TID

PTU 200 TIDSandostatin LAR 20 mg

Methimazole 30 mg QD

Sandostatin LAR 10 mg

Methimazole 30 mg QD

Pegvisomant 10 mg

Sandostatin LAR 10 mg

Methimazole 30 mg QD

Hemythyroidectomy

•IGF1

•TSH

•GH •FT4

Methimazole 10

Discussion

• Treat the hyperthyroidism?

• Maximize octreotide dose before re-starting pegvisomant?

• Re-evaluate the possibility of Neuro-surgery and/or XRT?

Discussion

• Treat the hyperthyroidism?

• Maximize Octreotide dose before re-starting pegvisomant?

• Re-evaluate the possibility of Neuro-surgery and/or XRT?

Is the Combination Worse?

4 patients with unsuppressed GH, when hyperthyroidism was diagnosed, had LVMi and worse LVEF(%) when compared to pts with controlled GH

Marzullo et. Al JCEM 2000, 85(4):1426-1432

Hyperthyroidism and Mortality

Parle et. Al Lancet 2001 358:861-865

Cappola et. JAMA 2006 295(9):1033-1041

Discussion

• Treat the hyperthyroidism?

• Maximize Octreotide dose before re-starting pegvisomant?

• Re-evaluate the possibility of Neuro-surgery and/or XRT?

• Normal IGF-1 values in 70% of pts.

• The best predictors of final hormonal values

- GH < 5

- IGF-1 500

• Tumor size was not predictive

• Basal hormonal levels at baseline were not predictive.

At six months of maximal therapy

Cozzi et. Al JCEM 2006 91(4):1397-1403

Discussion

• Treat the hyperthyroidism?

• Maximize Octreotide dose before re-starting pegvisomant?

• Re-evaluate the possibility of Neuro-surgery and/or XRT?

• Surgical tumor removal 75% enhances the response to SSA

Colao et. Al JCEM 2006 91(1):85-92

• Pt not a candidate for gamma-knife or any stereotactic XRT because of the tumor’s close proximity to the optic chiasm.

• No outcome reports of IMRT on pituitary adenomas.

Conclusions

• If pt fails maximal Octreotide therapy, re-start pegvisomant to maintain normal IGF-1 levels

• Continue Octreotide to normalize TSH to see if euthyroidism can be achieved without methimazole

• Consider IMRT

Thank You !