Department of Medical SciencesUniversity of Milan, Italy

Endocrinology and Diabetology Unit Fondazione Policlinico IRCCS

Milan, Italy

Paolo Beck-Peccoz

TSH-secreting pituitary adenomas

paolo.beckpeccoz@unimi.it

0

50

100

150

200

PureTSH-omas

GH PRL FSH/LH

72.2%

16.0%10.4%

1.4%

Nu

mb

er o

f ca

ses

TSH-omas mixed tumorBeck-Peccoz et al., Endocrine Reviews 1996;17:610–638.

Classification of TSH-secreting pituitary tumors

Euthyroid

Thyroid

Peripheral

tissue

Pituitary

TSH

T3T4

Hypothalamus

TRH

RTH

Peripheral

tissue

Pituitary

TSH

T3T4

TRH

Hypothalamus

Thyroid

Hyperthyroid

Peripheral

tissue

Pituitary

TSH

T3T4

TRH

Hypothalamus

Thyroid

& TSH-oma

Positive MRI in RTH patients

9 out of 22 (40%) patients with RTH showed the presence of a pituitary lesion at MRI/CT scan

Pituitary incidentaloma diagnosed in 8 cases

Possible association between RTH and TSH-omawas suspected, but not yet proved, in only one 62-yr-old woman

Nevertheless, the prevalence of pituitary incidentaloma appears higher in RTH patients (40%) than in the general population (20-30%)

Central Hyperthyroidism: serum levels of TSH and FT4Central Hyperthyroidism: serum levels of TSH and FT4

TSH mU/LTSH mU/L

Ser

um

FT

4 p

mol

/LS

eru

m F

T4

pm

ol/L

0.10.1 11 10101818

2727

3636

4545

5454

6363

RTH (n=59)TSH-omas (n=13)

CIRCULATING FACTORS MAY INTERFERE WITH MEASUREMENT OF TSH OR TOTAL AND FREE THYROID HORMONES

OVERESTIMATION OF SERUM LEVELS

CENTRAL HYPERTHYROIDISM?

Heterophylic Ab directed against mouse -globulins: interference

with monoclonal Ab used in the IRMA Anti-TSH Ab or Ab cross-reacting

with TSH

Anti-T4 and/oranti-T3 Ab

Abnormal forms of albuminor transthyretin (FDH)

DIFFERENTIAL DIAGNOSIS BETWEENTSH-OMAS AND RTH

•Age (years) 11-84 0.1-80 NS•Sex (F/M ratio) 1.28 1.17 NS•TSH mU/L 2.7±0.6 2.2±0.3 NS•FT4 pmol/L 40.0±4.2 29.5±2.5 NS•FT3 pmol/L 14.5±1.4 11.7±1.0 NS•SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001•Familial cases 0% 81% <0.0001•Lesions at CT scan or MRI 98% 10% <0.0001•High -subunit levels 65% 2% <0.0001•High -subunit/TSH m.r. 81% 2% <0.0001•Abnormal TSH response to TRH test 83% 4% <0.0001•Abnormal TSH response to T3 suppression test 100% 100% NS

PARAMETER TSH-omas RTH P

TSH biological activity in various thyroid disorders

RTHTSHomas

0

1

2

3

4

5

Cir

cula

tin

g T

SH

B/I

Persani et al., J Clin Endocrinol Metab. 1994; 78:1034–1039.

Net increments after TRH injection in RTHNet increments after TRH injection in RTH

FT4FT400

55

1010

1515

2020

pm

ol/L

pm

ol/L

**

FT3FT300

2.52.5

55

7.57.5

1010

pm

ol/L

pm

ol/L

**

TSHTSH00

1010

2020

3030

mU

/Lm

U/L

ControlsControls

RTHRTH* * PP<0.01 <0.01 vsvs controlscontrols

Beck-Peccoz&Persani, Eur J Endocrinol, 1994; 131:331-340

DIFFERENTIAL DIAGNOSIS BETWEENTSH-OMAS AND RTH

•Age (years) 11-84 0.1-80 NS•Sex (F/M ratio) 1.28 1.17 NS•TSH mU/L 2.7±0.6 2.2±0.3 NS•FT4 pmol/L 40.0±4.2 29.5±2.5 NS•FT3 pmol/L 14.5±1.4 11.7±1.0 NS•SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001•Familial cases 0% 81% <0.0001•Lesions at CT scan or MRI 98% 10% <0.0001•High -subunit levels 65% 2% <0.0001•High -subunit/TSH m.r. 81% 2% <0.0001•Abnormal TSH response to TRH test 83% 4% <0.0001•Abnormal TSH response to T3 suppression test 100% 100% NS

PARAMETER TSH-omas RTH P

DIFFERENTIAL DIAGNOSIS BETWEENTSH-OMAS AND RTH

•Age (years) 11-84 0.1-80 NS•Sex (F/M ratio) 1.28 1.17 NS•TSH mU/L 2.7±0.6 2.2±0.3 NS•FT4 pmol/L 40.0±4.2 29.5±2.5 NS•FT3 pmol/L 14.5±1.4 11.7±1.0 NS•SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001•Familial cases 0% 81% <0.0001•Lesions at CT scan or MRI 98% 10% <0.0001•High -subunit levels 65% 2% <0.0001•High -subunit/TSH m.r. 81% 2% <0.0001•Abnormal TSH response to TRH test 83% 4% <0.0001•Abnormal TSH response to T3 suppression test 100% 100% NS

PARAMETER TSH-omas RTH P

DIFFERENTIAL DIAGNOSIS BETWEENTSH-OMAS AND RTH

•Age (years) 11-84 0.1-80 NS•Sex (F/M ratio) 1.28 1.17 NS•TSH mU/L 2.7±0.6 2.2±0.3 NS•FT4 pmol/L 40.0±4.2 29.5±2.5 NS•FT3 pmol/L 14.5±1.4 11.7±1.0 NS•SHBG nmol/L 113.0±17.2 62.0±4.0 <0.0001•Familial cases 0% 81% <0.0001•Lesions at CT scan or MRI 98% 10% <0.0001•High -subunit levels 65% 2% <0.0001•High -subunit/TSH m.r. 81% 2% <0.0001•Abnormal TSH response to TRH test 83% 4% <0.0001•Abnormal TSH response to T3 suppression test 100% 100% NS

PARAMETER TSH-omas RTH P

Acute somatostatin analog injectionAcute somatostatin analog injection

-50-50

-25-25

Var

iati

ons

(% o

f b

asal

val

ues

)V

aria

tion

s (%

of

bas

al v

alu

es)

+25+25

00

+50+50 TSHTSH FT4FT4 FT3FT3

RTHRTH

TSH-omasTSH-omas

Mannavola et al., Clin Endocrinol 2005; 62: 176-181

2-3 months somatostatin analog administration2-3 months somatostatin analog administration

-50-50

-25-25

Var

iati

ons

(% o

f b

asal

val

ues

)V

aria

tion

s (%

of

bas

al v

alu

es)

+25+25

00

+50+50TSHTSH FT4FT4 FT3FT3

RTHRTH TSH-omasTSH-omas

Mannavola et al., Clin Endocrinol 2005; 62: 176-181

In summary:

normalelevated SHBG and -sub

negativepositive Imaging

NO YESFamily members

YESNO

YESNO

YESNO

TRH test

T3-suppression test

TRH test post T3

TRNO Molecular study

FT3 & FT4 two step

or TSH Ultrasensitive methods

TSH-oma

RTH

0

5

10

15

20

25

30

35

40

45

50

All patients Previousthyroidablation

No thyroidablation

Per

cen

t of

cas

es

IntrasellarExtrasellarInvasive

Different therapeutical approaches

• None• TH analogsTRIAC, DT4,

GC1 (binds wtTR>TR), HY1 (acts on TR mut

R320C)• Cardiac selective blockers• Inhibition of mutant gene

expression

• Neurosurgery

• Radiotherapy

• SRIH analogsOctreotideLanreotideSOM 230

RTH TSH-oma

Reduction of tumor mass

• complete 34% 29% 0%

• partial 34% 40% 51%

• absent 32% 31% 49%

Resolution of clinical symptoms

• yes 57% 62% 95%

• no 43% 38% 5%

Surgery Surgery +Rx SMS analogs (n=125) (n=57) (n=84)

TSH producing adenomas: results ofdifferent therapeutic approaches

0.1

1

10

1 2 3 4 5 6 7 8 9 10 11 12 13 14

T3 suppression test

Baseline

T3 suppression test

Baseline

Patients withintact thyroid

Patients withthyroid ablation

Case #

Before neurosurgery After neurosurgery

Se

rum

TS

H m

U/L

Results of chronic somatostatin analog treatmentof TSH-secreting pituitary adenomas

TSH/-GSU reduction 92% Thyroid hormone normalization 95% Vision improvement 75% Tumor mass shrinkage 52% True resistance 4% Discontinuation due to side effects 10%

00

55

1010

1515

2020

2525

3030

3535

4040

00 22 44 66 1212 2424

TSHTSHa-GSUa-GSU

FT4FT4

FT3FT3GHGH

MonthsMonths

Hor

mon

e le

vels

Hor

mon

e le

vels

Hormone levels after somatostatin analog Hormone levels after somatostatin analog in one patient with mixed GH/TSH adenomain one patient with mixed GH/TSH adenoma

IGF-I normalizedafter 2 months

ACKNOWLEDGEMENTS

Luca Persani Deborah Mannavola

Irene CampiLaura Fugazzola Guia VannucchiMarco Bonomi Andrea LaniaSabrina CorbettaGiovanna MantovaniCarmela Asteria

Krishna ChatterjeeSamuel RefetoffAnna Spada