Clinical case

2003…

A 30 year-old woman…...admitted to our hospital due to obesity

and diabetes mellitus...

UFC: 120-140-135 µg/24h (1900-2100 cc) (20-90 µg/24 h)

Morning cortisol: 25.6-30.6 µg/dl (5.0-20 µg/dl)

Morning ACTH: 57-61 pg/ml (8-53 pg/ml)

Midnight plasma cortisol: 28.8-30.2 µg/dl

1 mg DEX test: cortisol 11.4 µg/dl

Liddle I test: cortisol 7.5 µg/dl

Diagnosis of Cushing’s disease

8 mg DEX test: cortisol 4.6 µg/dl

hCRH test: cortisol peak vs baseline: 36.5 vs 25.8 µg/dl (41% increase)

ACTH peak vs baseline: 91.5 vs 58.7 pg/ml (55.8% increase)

Clinical feature:

- Moon shaped face, cervical fat pad, supraclavicular fat accumulation, central fat distribution, thinned skin with easy bruising- Metabolic syndrome (visceral obesity BMI 35 kg/m2, DM without

complications, hypertension without complications, dislipidemia)

Other Exams…Other Exams…

• HbA1c: 6.8% (Metformin 1500 mg/die)

• Tot col: 214 mg/dl, HDL: 54 mg/dl, TG 200 mg/dl, LDL: 120 mg/dl

• Creatinine: 0.6 mg/dl, urea: 22 mg/dl, creatinine clearance: 81 ml/min, albuminuria: negative

• Na: 139 mmol/l, K: 3.8 mmol/l

• AST: 16 U/l, ALT: 20 U/l, GGT: 47 U/l

• Echocardiography: normal range

• Carotid doppler ultrasound: intimal thickenings along the common carotid artery, without flow alterations; carotid intima-media thickness <0.9 mm

• Retina evaluation: no diabetic or hypertensive alterations

• DEXA: normal (lumbar T score + 0.4)

Pituitary Imaging

Therapy

Resection of the pituitary adenoma by transsphenoidal surgery ( April 2003)

Immunoistochemistry: pituitary adenoma, positive for ACTH Ki-67 <1%, P53 negative

UFC: 21 µg/24h (1900-2100 cc) (20-90 µg/24 h)

Morning cortisol: 7.5 µg/dl (5.0-20 µg/dl)

Morning ACTH: 19.4 pg/ml (vn 8-53 pg/ml)

Midnight plasma cortisol: 7.1 mcg/dl

1 mg DEX test: cortisol 3.6 µg/dl

Patient re-tested 2 weeks later (washout cortisone 25 mg po 3 days before)

No symtoms of acute hypoadrenalism

Remission not complete…

TSH: 0.9 mU/l, fT4: 9.4 pg/ml, fT3: 3.1 pg/ml

UFC: 32 µg/24h (1900-2100 cc) (20-90 µg/24 h)

Morning cortisol: 15.3 µg/dl (5.0-20 µg/dl)

Morning ACTH: 32.8 pg/ml (vn 8-53 pg/ml)

Midnight plasma cortisol: 8.1 mcg/dl

…re-tested 3 months later…

No symtoms of hypoadrenalism, occurrence of menses

FSH: 3.2 mU/l, LH: 5.6 mU/l, E2: 80 pg/ml

PRL: 15 ng/ml

TSH: 1.6 mU/l, fT4: 10.8 pg/ml, fT3: 3.3 pg/ml

IGF-I: 215 µg/l

DM improved: HbA1c 5.8% (same therapy)Lipid profile improved: LDL 100 mg/dlBlood pressure improved (same therapy)

BMI unchanged: 35 kg/m2

1 mg DEX test: cortisol 5.8 µg/dl

Pituitary Imaging

What can be done?

……she showed a good biochemical and clinical profile for 2 she showed a good biochemical and clinical profile for 2 years…years…

…the patient underwent a periodic follow up…

…January 2006…

Weight increase (BMI 37 kg/m2)DM worsening (HbA1c 8.5%) Lipid profile worsening (LDL 130 mg/dl)Blood pressure worsening (>130/80 mm Hg)

UFC: 105-103 µg/24h (1900-2100 cc) (20-90 µg/24 h)

Morning cortisol: 22.0 µg/dl (5.0-20 µg/dl)

Morning ACTH: 28.4 pg/ml (vn 8-53 pg/ml)

Midnight plasma cortisol: 16.4 µg/dl

Pituitary Imaging: unchanged.

What can be done?

Second-line therapeutic options in persistent disease after transsphenoidal surgery

Repeat pituitary surgerylow rate of success (50-70%) in comparison with the first operationrisk of pituitary insufficiency

Radiotherapyremission rate 53-100%need of other treatments in the “interim” periodrisk of pituitary insufficiencyrisk of CNS complications

Medical therapynot definitive therapyvariable rate of success (different drugs, site of action, doses)

Bilateral adrenalectomydefinitive treatmentneed of lifelong hormonal replacement therapyrisk of Nelson’s syndrome From: Biller et al, JCEM 2008

Clinical variables influencing the choicein persistent disease after transsphenoidal surgery

Age

Entity of hypercortisolism

Comorbidities

Presence/absence of pituitary deficiencies

Pituitary imaging

Risk of Nelson’s syndrome

Patient’s compliance

Second-line therapeutic options in persistent disease after transsphenoidal surgery

Repeat pituitary surgerylow rate of success (50-70%) in comparison with the first operationrisk of pituitary insufficiency

Radiotherapyremission rate 53-100%need of other treatments in the “interim” periodrisk of pituitary insufficiencyrisk of CNS complications

Medical therapynot definitive therapyvariable rate of success (different drugs, site of action, doses)

Bilateral adrenalectomydefinitive treatmentneed of lifelong hormonal replacement therapyrisk of Nelson’s syndrome From: Biller et al, JCEM 2008

UFC 43-58-95-81-110 µg/24h (1900-2100 cc) (20-90 µg/24 h)

…medical therapy with ketoconazole (400 mg/die) was started…

Metabolic profile firstly improved but later worsened…

…at 12 months:Weight (BMI 36 kg/m2)HbA1c 8.1% (LDL 121 mg/dl)Blood pressure not well controlled

…during the following 12 months…

What can be done?

UFC 115-102-90-85-95-99 µg/24h (1900-2100 cc) (20-90 µg/24 h)

…cabergoline (up to 3.5 mg/week) was added…

Metabolic profile was not significantly modified…Therapy with metformin was increased (up to 2500 mg/die) and atorvastatin (10 mg/die) was added…

…during the following 6 months…

What can be done?

… the patient showed no compliance to increased medical therapy and asked for a more definitive treatment …

… she underwent a bilateral adrenalectomy … (January 2008)

…at the last follow up (2011):

• BMI improved: 31 kg/m2

• DM improved: HbA1c 6.7 during Metformin 1000 mg/die

• Lipid profile improved: Tot col 162 mg/dl, HDL 55 mg/dl, TG 158 mg/dl, LDL 75 mg/dl during atorvastatin 10 mg/die

• Blood pressure normalized medical therapy was stopped

Pituitary Imaging

…mild hypercortisolism needs to be counteracted in patients with persistent disease after transsphenoidal

surgery…

…the best balance between the negative influence of hypercortisolism and the risk of the different treatments

must be found, expecially in young patients without hypopituitarism…

…the choice of medical therapy should take into account not only efficacy and safety, but also over-treatment risk

and patient’s compliance…