Definition
- Endogenous hypercortisolism due to hypersecretion of ACTH by an ACTH-secreting pituitary adenoma
General
- ACTH secreting tumour
- Caused by an adrenocorticotropin (ACTH)-secreting pituitary tumour
Numbers
- 40/4million
- ACTH producing adenomas is 10-12% of Pituitary adenomas
- 9:1 F:M
- At presentation 50% of patients with Cushing disease have Pituitary tumours of<5mm
- Hard to image on CT or MRI
- 10% of tumours are large enough to produce mass effect → mass effect symptoms
Genetics of CD
- Corticotroph adenomas are predominantly of sporadic origin
- A monoclonal expansion of a singular mutated cell
- Abundantly express EGFR, which signals to induce ACTH production
- Somatic activating driver mutations in USP8 are present in 36–60% of corticotroph adenomas → persistent overexpression of EGFR → hypersynthesis of ACTH
- Not really associated with familial tumor syndromes, such as MEN1, FIPA, and DICER1
Clinical presentation of hypercortisolism
General
- Cyclical Cushing disease: hyperplasia
- Mortality
- Obstructive Cardiac myopathy
- Colon cancer
Immunity
- Sepsis: associated with advanced Cushing’s syndrome
- Increased risk for infection
- Hypercortisolism remission can induce exacerbation of pre-existing autoimmune disorders.
Hypercoagulability
- Hypercoagulability in CS resulting in increased risk of thromboembolic events (TE) is paradoxically coupled with an increased bleeding tendency due to skin atrophy and capillary fragility
- Most patients show an activated coagulation cascade, including shortened activated partial thromboplastin time and increased fibrinogen, von Willebrand factor, and factor VIII, as well as impaired fibrinolysis mediated by elevated plasminogen activator inhibitor-1 and antiplasmin. Increased thrombin, thromboxane 2, and platelets, with a compensatory increase in anti-coagulation factors such as protein C and S, have also been implicated
- VTE
- Incidence in patients with endogenous CS is
- 10x higher vs those with nonfunctioning adenomas undergoing surgery
- 18x higher compared with the healthy population
- VTE risk persists in the first few months after CD surgery
- Indicating that hypercoagulability is not immediately reversible with cortisol normalization
- Thromboprophylaxis can decrease the incidence of postoperative VTE, particularly when extended to 30 days
Cardiovascular Disease
- CD has an adverse cardiovascular disease risk profile that may persist even after successful treatment
- Aetiology
- Visceral, subcutaneous, and total fat may decrease after remission, although most patients remain overweight or obese
- T2DM is present in up to 30% of CD patients
- Most T2DM resolves after remission of CD
- Dyslipidemia, with low HDL, high LDL, and high triglycerides in 16–64% of CD cases
- Structural cardiovascular changes
- Such as
- Left ventricular hypertrophy,
- Concentric remodelling,
- Dilated cardiomyopathy,
- Increased intima media thickness,
- Increased formation of atherosclerotic plaques,
- Can lead to
- Hypertension
- Heart failure
- Improve but may not fully resolve despite remission of hypercortisolism
- Myocardial infarction, stroke, and other vascular events are a primary cause of increased standardized mortality ratio (SMR; 4.1 to 16) in patients with active/persistent CD
- These rates do not entirely normalize, but are lowered upon remission
Bone Disease
- Skeletal fragility is a frequent and early complication of hypercortisolism, and fractures may be the first clinical manifestation of the disease
- Vertebral fractures occur in 30–50% of patients
- Correlates with hypercortisolism severity.
- Mechanism
- Hypercortisol →
- Suppresses
- GH/IGF-I
- Hypothalamic-pituitary-gonadal axes
- Alters
- PTH pulsatility
- Leading to decreased osteoblast number and function,
- As evidenced by decreased serum levels of osteocalcin and alkaline phosphatase
- DEXA can be normal in CS
- BMD increases were reported after hypercortisolism resolution, some patients show persistently high fracture risk, with men at higher risk compared with women
- Management
- Conventional osteoporosis treatments, e.g., bisphosphonates, as well as supportive treatment with vitamin D and calcium may induce a more rapid improvement in BMD than cortisol normalization alone, and could be useful in patients with persistent postsurgical hypercortisolism to prevent further bone loss
Growth Hormone Deficiency (GHD)
- Glucocorticosteroids both endogenous and exogenous, inhibit GH secretion
- Cortisol → inhibit GGH secretion → decreasing IGF-I production by the liver
- GH production can be fully restored in most patients after successful therapy and recovery of HPA axis, even years after remission, persistence of GH deficiency (GHD) can potentially worsen hypercortisolism complications such as bone loss, myopathy, and memory deficits.
- Test
- Insulin tolerance test
- Glucagon stimulation test
- GHD prevalence in adults varies with timing of the diagnosis, ranging from
- 50–60% when testing was performed within 2 years after surgery TO
- 8–13% when done more than 2 years after surgery
- IGF-I is an insensitive screening test for diagnosing GHD in adults.
- Compared with other GHD etiologies, GHD in patients with CS is more common in
- Women and younger patients;
- Exhibit higher rates of
- T2DM,
- HTN
- Low bone mass & Fractures
- Worse QoL
- Myopathy
- May be partially related to GHD among patients in remission.
- Preoperative IGF-I levels during active CS did not predict long-term myopathy risk
- Lower 6-month postoperative IGF-I levels predict more severe long-term muscle atrophy and weakness after CS remission
- GH replacement
- Ameliorates
- A number of complications associated with metabolic syndrome
- Risk for cardiovascular and cerebrovascular disease.
- Studies have shown GH replacement
- To
- Decreased body weight
- Waist circumference
- Total and LDL-cholesterol
- QoL and BMD improvement
- But if patient has pre-existing glucose intolerance, it may worsen glucose metabolism
Myopathy
- Test
- Impaired stair climbing and straightening up
- Pathophysiology (multifactorial)
- Protein degradation through the forkhead box O3 (FOXO3) pathway
- Accumulation of intramuscular fat
- Inactivity-associated muscle atrophy
Weight gain
- 50% of cases
- Centripetal fat deposition 50%: trunk, upper thoracic spine (“buffalo hump”), supraclavicular fat pad, neck, “dewlap tumour” (episternal fat), with round plethoric face (“moon facies”) and slender extremities
- SLEEP APNEA
Psychiatric and psychological
- Affective disorders
- Cognitive dysfunction
- Negative illness perception
- These can be persistent even after CD treatment
Skin/mucosa
- Atrophic, tissue-paper thin skin with easy bruising and poor wound healing
- Stretch marks
- Due to cortisol decreasing collagen lay down
- Hyperpigmentation of skin and mucous membranes:
- Due to MSH cross-reactivity of ACTH. Occurs only with elevated ACTH, i.e., Cushing’s disease (not always in Cushing’s syndrome) or ectopic ACTH production (also below)
- Ecchymoses and purple striae, especially on flanks, breasts, and lower abdomen
- Elevation of other adrenal hormones:
- Androgens may produce hirsutism and acne
Other complications
- Dysfunction of one or more pituitary axes such as central hypothyroidism
- Gonadal function impairment → infertility
- Amenorrhea in women, impotence in men, reduced libido in both
Management
General
- Achieve <100 nmol/l cortisol to achieve remission
Management algorithm
- MRI pituitary
- Mass on MRI → transsphenoidal surgery
- Surgery done but biochemical cure is not achieved:
- Re-exploration if pituitary source is still suspected
- Unlike acromegaly, a partial reduction is not helpful to the patient
- Stereotactic radiosurgery or medical therapy
- Adrenalectomy in appropriate patients
- MR shows no Mass (40% of patients with Cushing’s disease have negative MRI):
- Perform inferior petrosal sinus (IPS) sampling
- Aim for IPS:
- To define it is cranial (100%)
- To define it is left or right pituitary (60%) - but not always correct to tell which side it is
- Because there is a intercavernous sinus that allows for both sides to have raised levels
- If IPS sampling is positive: surgery
- If IPS sampling is negative: look for extra-pituitary source of ACTH (abdominal CT)
Medical therapy
- Treatment via Medical therapy is inadequate as initial therapy since there is no effective pituitary suppressive medication
Indication
- Fail surgical therapy
- Persistent CD
- Recurrent CD
- Cannot tolerated surgery
- Control cortisol levels in patients undergoing radiation therapy (RT)
- Preop (for several weeks) to control manifestations of hypercortisolism (diabetes, HTN, psychiatric disturbances).
All patients require monitoring
- Regular monitoring with
- Measures of cortisol (except with mifepristone)
- 24hr Urine free cortisol
- Late night saliva cortisol
- 9am Cortisol
- Patient symptoms and comorbidities,
- Especially weight, glycemia, and blood pressure
Target
- Adrenal
- Ketoconazole (Nizoral®): drug of choice.
- Indicated
- 1st line treatment
- Preoperative therapy- temporarily lower cortisol levels
- An antifungal agent that blocks multiple adrenal enzymes
- Also shuts down gonadal steroids synthesis
- Outcome
- > 75% of patients have normalization of urinary free cortisol and 17-hydroxycorticosteroid levels.
- Side effects:
- Elevations of serum hepatic transaminase (15%)
- Appears within the first 6 months of treatment
- Seem not to be dose-dependent
- Reverse within 2–12 weeks after dose decrease or discontinuation.
- Do weekly monitoring
- GI discomfort 10%
- Skin rash 5%
- Significant hepatotoxicity occurs in 1/15,000 patients.
- Men : hypogonadism and gynecomastia
- Shut down of gonadal steroids synthesis
- Dose
- 200mg PO BD → inc. to max of 1600mg/day.
- Adjust dosage based on 24-hr urine free cortisol and 17-hydroxycorticosteroid levels.
- Evidence
- UFC normalization in 60% but 20% of these pt loose biochemical control eventually
- Metyrapone (Metopirone®):
- Indicated
- Preoperative therapy
- Inhibits 11-β-hydroxylase (involved in one of the final steps of cortisol synthesis)
- May be used alone or in combination with other drugs.
- 11-deoxycortisol may produce clinically relevant cross-reactivity with cortisol in both blood and urine immunoassays
- Outcome
- Normalizes mean daily plasma cortisol in 75%.
- Side effects:
- Lethargy
- Dizziness
- Ataxia
- N/V
- Primary adrenal insufficiency
- Hyperandrogenism
- Hirsutism
- Acne
- Dose
- 750–6000mg/d PO TDS with meals.
- Initial effectiveness may diminish with time.
- Evidence
- UFC normalization in 70%
- 20% escaping after initial response.
- 11β-hydroxylase and aldosterone synthase inhibitor
- Indicated for severe CD
- Side effects
- Nausea, anaemia, and headache 8–11%
- Hypocortisolism symptoms 50%
- 11% of women reported hirsutism
- Improvements seen in clinical features, cardiovascular disease markers, and QoL
- Evidence
- UFC normalization in 86%
- "No data" escaping after initial response
- Related to the insecticide DDT.
- Indication:
- Not used for CD
- Mainly used in adrenal carcinoma
- Mech
- Inhibits several steps in glucocorticoid synthesis, and is cytotoxic to adrenocortical cells (adrenolytic agent).
- Has a long-lasting adrenolytic action in steroid-secreting adrenocortical cells
- Outcomes
- 75% of patients enter remission after 6–12 months of treatment,
- The medication may be discontinued (kills cells) → risk of hypercortisolism.
- Side effects: may be limiting
- Anorexia,
- Lethargy,
- Dizziness,
- Impaired cognition,
- GI distress,
- Hypercholesterolemia,
- Adrenal insufficiency
- (Which may necessitate supernormal doses of glucocorticoids for replacement due to induced glucocorticoid degradation).
- Induction of CYP3A4-mediated rapid inactivation of cortisol leads to a requirement for a 2- to 3-fold increased GC replacement dose when treatment of AI is needed or with a block-and-replace strategy
- Dose
- 250–500mg PO ON → slowly rise to 12,000g/d in split doses.
- Initial effectiveness may diminish with time.
- An anesthetic agent
- Low-dose etomidate (0.04–0.05 mg/kg/h) produces partial blockade; a high-dose (0.5–1 mg/kg/h) provides for complete blockade
- With IV hydrocortisone used to avoid etomidate-induced AI
Steroidogenesis inhibitors (1st line)
Osilodrostat
Mitotane (Lysodren®)
Etomidate
- Pituitary: used in CD patients with persistent or recurrent hypercortisolism
- Pasireotide
- Somatostatin receptors agonist
- UFC normalized at month 6 in 15–26% of without dose increases
- Decreased median tumor by 20%
- Side effects
- Risk for hyperglycemia is high 70%
- Cabergoline
- Indicated
- Mild CD
- Mech
- Dopamine 2-type receptors
- Present in 80% of pituitary corticotropic adenomas → Cabergoline reduce ACTH secretion
- Evidence
- Biochemical normalization in 25–40% of patients, with loss of control in 20–40% initially normalized.
- Side effects
- Cabergoline-induced impulse-control disorder is likely under-reported,
- Such as
- Hypersexuality
- Pathological gambling
- Excessive alcohol consumption
- Overeating,
- Uncontrolled shopping
- Can occur at any time during initiation, after initiation and even after stopping cabergoline
- Cardiac valve regurgitation
Somatostatin receptors
Dopamine receptor agonist
- Rest of body
- Mifepristone
- Glucocorticoid receptor blocker
- Side effects
- Increased blood pressure,
- Hypokalemia
- Due to mineralocorticoid receptor activation
- Endometrial hypertrophy and irregular menstrual bleeding
- Due to antiprogesterone activity
GC receptors
Aminoglutethimide (Cytadren®)
- Inhibits the initial enzyme in the synthesis of steroids from cholesterol.
- Outcome
- Normalizes urinary free cortisol in 50% of cases.
- Side effects:
- Dose-dependent reversible effects include sedation,
- Anorexia,
- Nausea,
- Rash
- Hypothyroidism (due to interference with thyroid hormone synthesis).
- Dose
- 200mg PO BD → 1000mg/d
- Effectiveness may diminish after several months and dose escalation may be needed.
Cyproheptadine (Periactin®)
- A serotonin receptor antagonist that corrects the abnormalities of Cushing’s disease in a small minority of patients, suggesting that some cases of “pituitary” Cushing’s disease are really due to a hypothalamic disorder.
- Combined therapy with bromocriptine may be more effective in some patients.
- Side effects:
- Sedation & hyperphagia with weight gain usually limit usefulness.
- Dose
- 8–36mg/d divided TDS.
Summary tables
Name | ketoconazole | Aminoglutethimide | Metyrapone | Mitotane | Cyproheptadine |
Mech | Antifungal agent blocks adrenal steroid synthesis | Inhibits the initial enzyme in the synthesis of steroids from cholesterol | Inhibits 11-β-hydroxylase (involved in one of the final steps of cortisol synthesis) | • Related to the insecticide DDT. • Inhibits several steps in glucocorticoid synthesis, and is cytotoxic to adrenocortical cells (adrenolytic agent). | • A serotonin receptor antagonist that corrects the abnormalities of Cushing’s disease in a small minority of patients, suggesting that some cases of “pituitary” Cushing’s disease are really due to a hypothalamic disorder. |
Effectiveness | > 75% of patients have normalization of urinary free cortisol and 17-hydroxycorticosteroid levels. | Normalizes urinary free cortisol in 50% of cases | Normalizes mean daily plasma cortisol in 75%. | 75% of patients enter remission after 6–12 months of treatment | |
Side effect | • Reversible elevations of serum hepatic transaminase (15%) • GI discomfort • Edema • Skin rash • Significant hepatotoxicity occurs in 1/15,000 patients. | • Dose-dependent reversible effects include sedation, • Anorexia, • Nausea, • Rash • Hypothyroidism (due to interference with thyroid hormone synthesis). | • Lethargy • Dizziness • Ataxia • N/V • Primary adrenal insufficiency • Hirsutism • Acne | • Anorexia, • Lethargy, • Dizziness, • Impaired cognition, • GI distress, • Hypercholesterolemia • Adrenal insufficiency | • Sedation & hyperphagia with weight gain usually limit usefulness. |
Starting dose | 200mg PO BD | 200mg PO BD | 750–6000mg/d PO TDS with meals | 250–500mg PO ON | 8–36mg/d divided TDS |
Transsphenoidal surgery
General
- Treatment of choice and 1st line treatment for CD
- For microadenomas, Hemihypophysectomy on the side of the tumour is usually required for cure (the tumour is difficult to completely extirpate)
- Aggressive surgical approach because
- ACTH is harmful
- Effective medical therapy is lacking
- Pre-treat invasive GH-secreting tumours with somatostatin analogue therapy before surgery to reduce surgical risks (general and cardiac)
Aim
- Remission of CD
- Postoperative serum cortisol <55 nmol/L (<2 μg/dL)
Post op
- GC replacement until HPA axis recovery
- Monitoring for recurrence
- Recurrence: reappearance of clinical and biochemical features of hypercortisolism following initial remission
- Lifelong monitoring required
- Low or undetectable cortisol in the immediate postoperative period is a defining criterion of remission, but does not necessarily predict lack of recurrence
- Recurrence rates
- 5% and 35%
- 50% appearing within the first 5 years post op
- 50% appearing more than 10 years post op
- Test
- In patients with no evidence of cortisol deficiency before operation:
- Check 9 am serum cortisol on day 2 and on day 3 after surgery
- If already on hydrocortisone replacement, omit the evening dose for the previous day before checking.
- Do late night saliva cortisol
- Compared to their use in the initial diagnosis of CS, late night Saliva Cortisol, 1-mg DST, UFC, and desmopressin tests have a lower sensitivity for recurrence, but specificity is high, up to 95% or more
- Late night saliva cortisol is the fastest to detect recurrence
- Urine Free Cortisol is the slowest to detect recurrence
- Treatment options
- If initial hemihypophysectomy fails → repeat scan and if there is evidence of recurrent CD with visible tumor on MRI → repeat surgery
- Best not to do revisional surgery if no tumour visible on MRI
- If fails, total hypophysectomy.
- Total hypophysectomy virtually eliminates risk of Nelson’s syndrome following adrenalectomy.
- If fails, total bilateral adrenalectomy (TBA)
- Outcome: corrects hypercortisolism in 96–100%
- Unless there is an extraadrenal remnant
- Lifelong gluco- and mineralo-corticoid replacement are required
- 30% develop Nelson’s syndrome (incidence reduced by total hypophysectomy or possibly by pituitary XRT).
- Indications: continued hypercortisolism with:
- Non-resectable pituitary adenoma
- Failure of medical therapy to control symptoms after transsphenoidal surgery
- Life-threatening Cushing’s disease (CD)
- CD with no evidence of pituitary tumour;
- Testing should include
- High-dose DMZ suppression test and/or
- Inferior petrosal sinus sampling
- Follow-up
- To rule out Nelson’s syndrome
- Check serum ACTH levels
- 1st year: 3–6 months
- 2nd & 3rd year: 6 months
- 4th+ yr : annually
- Pituitary MRI done
- If an ACTH level is >100 ng/L; otherwise
- Annual MRIs are sufficient first 3 years → alternate years MRI if ACTH levels remain low
- Other options
- Radiotherapy
- Bilateral adrenalectomy
- Offers immediate control of cortisol excess in patients
- Indication
- Persistent or recurrent CD not responsive to medical therapy
- Cons
- Causes resultant AI → need for life-long GC and mineralocorticoid replacement therapy
- Corticotroph tumour progression after BLA is a long-term concern in 25–40% of patients after 5 to 10 years
- Can lead to Nelson syndrome
- Watch out for vision deterioration as a result of growth of pituitary lesion
- Delayed Nelson syndrome due to ectopic ACTH formation (Eg: paraneoplastic from a new lung Ca)
- Outcome
- 10–18% complication rate
- <1% mortality rate
- Long-term clinical relapse of hypercortisolism due to adrenal rest stimulation by high ACTH is uncommon (<10%),
- Clinical improvement in BMI, T2DM, hypertension, and muscle weakness is reported in more than 80%
Risk
- New-onset hypopituitarism (11.5%)
- Permanent diabetes insipidus (DI) 4%
- CSF leak 13%
- VTE 1.5%
- Peri-operative mortality is <1%
Operative plan
- Elderly patients or tumours> 4cm diameter:
- Debulk tumour transsphenoidally and/or adjuvant therapy (XRT and/or medications)
- Young age and size < 4cm:
- Radical surgery (may utilize a cranio-orbito-zygomatic skull base approach; may be curative)
Number of cases to be considered expert
- Survey data demonstrate that neurosurgeons who have performed more than 200 TSS have the lowest complication rates.
- Regionalized neurosurgery 4–5 experts per 2.5–5 million inhabitants is the best
Outcome
- Remission rate
- Stroud et al 2020
- Primary surgery
- All: 80%
- Microadenomas: 83%
- Macroadenomas: 68%
- Revisional surgery
- 58%
- Higher remission rates with the following factors
- Detection on MRI
- Non-invasiveness
- Size <1 cm
- Recurrence rates
- Stroud et al 2020
- Primary TSS: 18%
- Revision TSS: 28%
- 20% microadenoma
- 40% macroadenoma
Comparison between micro vs endoscopic surgery for CD
- Bottom line no not much difference depends on surgeon preference but no reason why we should continue doing microscopic surgery
Stereotactic radiosurgery
- Often normalises serum cortisol levels.
- Indication (used as adjuvant)
- Recurrence after surgery
- Residual disease
- Inaccessible tumours (e.g. cavernous sinus)
- SRS As first line for high surgical risk patients and who refuse surgery
- Outcome
- Adjuvant (EBRT/SRS)
- 2/3 patients achieve biochemical remission during the years after treatment
- First line
- 81% biochemical remission at 5 years
- Dose
- Conventional external-beam RT (EBRT):
- 45–50 Gy administered in <2 Gy fractions
- SRS: (GammaKnife, LINAC, proton beam)
- A single dose or a few fractions of approximately 20 Gy
- Distance of at least 3–5 mm between the tumour and the optic chiasm and a chiasm dose <8 Gy is recommended to limit treatment damage.
- Given the latency until post-RT remission, adjuvant medical therapy is needed to control hypercortisolism;
- Periodic withdrawal allows cortisol secretion evaluation to assess treatment effect
- Use of Ketoconazole or cabergoline treatment at the time of SRS limits efficacy, they are often withheld temporarily at the time of RT.
- Side effects
- Hypopituitarism (25-50%)
- Risk of secondary malignancy, cranial nerve damage, and stroke are low with SRS.
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