Pituitary Problems



    Approach to Pituitary Hormones


    Review Hypothalamic Function

    • Anterior Pituitary
      • Hormones:
        • CRH --> ACTH
        • GnRH --> LH/FSH
        • TRH --> TSH
        • GRH --> Growth Hormone
      • Travel down hypothalamus down pituitary stalk + relased into pituitary gland.
      • Any pathological disruption of the stalk --> blocks hormone transmission down the stalk
        • EXCEPT Prolactin is different, it is under chronic inhibitory control from dopamine
        • If no dopamine released, prolactin will go up!
    • Posterior Pituitary
      • Neuronal Axons from supraoptic and paraventricular nuclei of the hypothalamus through the stalk.
      • Hormones released:
        • ADH
        • Oxytosin


    Hormone Excess

    • Hormone



      Initial Test
      ACTH Cortisol

      24hr urine cortisol (x2)

      Nocturnal Salivary Cortisol (x2)


      Overnight low dose dexamethasone test

      ADH ADH Simultaneous Serum+Urine Sodium and urine osmolality
      GH IGF-1 IGF-1
      TSH T4, T3 TSH + Free (or total) T4


    Hormone Deficiency

    • Hormone Peripheral Hormone Initial Tests Confirmatory Test
      ACTH Cortisol ACTH + Cortisol ACTH Stimulation Test
      ADH ADH Serum+urine sodium and serum osmolality Water Deprivation Test
      LH + FSH Sex Hormones LH, FSH, Testosterone (male), estriol (female)  
      TSH T4, T3 TSH, free (or total) T4  

    Anatomy Review

    • Hormone Origin Regulation
      ACTH Ant. Pit. + CRH
      TSH Ant. Pit + TRH
      LH, FSH Ant. Pit + GnRH pulses
      Prolactin Ant. Pit - Dopamine
      GH Ant. Pit Somatostatin

    • Imaging of pituitary is only done via MRI using a pituitary protocol (too small for other imaging)



    • With radiation to brain, hormones drop out in order (least important to most important):
      • 1. GH
      • 2. FSH/LH
      • 3. TSH
      • 4. ACTH
    • Causes:  (most acquired, rare genetic causes exist)
      • Tumors
        • (pituitary adenomas, craniopharyngiomas, dysgerminomas, meningiomas, gliomas, metastatic tumors, Rathke cleft cysts)
        • Metastasis commonly from Breast & Lung
      • Radiation
      • Trauma (neurosurgery, or external/blunt)
      • Infiltrative (Sarcoidosis, Langerhans cell histiocytosis, TB)
      • Empty Sella
      • Vascular (apoplexy, Sheehan syndrome, subarachnoid hemorrhage)
      • Lymphocytic hypophysitis (Pregnancy related hypertrophy, ACTH problem)
      • Metabolic causes (hemochromatosis, critical illness, malnutrition, anorexia nervosa, psychosocial deprivation)
      • Idiopathic
    • Investigations:
      • 8-9AM cortisol
      • 9am testosterone or estradiol (LH + FSH)
      • TSH Free T4
      • Prolactin
      • IGF-1
      • Na, POsm, UOsm, Spec Gravity (Polyuria hx more important)
    • Overall Approach to Tumors!
      • If you see a sellar mass = means NON Pituitary!
        • Treatment is surgery!!! (debulking to remove pressure on pituitary)
        • Can improve pituitary symptoms or worsen them (if resect normal tissue)


    Pituitary Masses

    • Types:
      • Somatotrophs (Growth Hormone)
      • Corticotrophs (ACTH)
      • Gonadotrophs (LH/FSH)
      • Lactrotrophs (Prolactone) - Most common functional
      • Thyrotrophs (TSH)
      • Non-Functioning Adenoma (MOST COMMON!!)
    • Pituitary adenomas do not usually produce diabetes insipitus.  If they do, then suspect an extra-sellar origin (craniopharyngeoma, rathke cleft cyst, metastatic neoplasm).

    Pituitary Adenoma

    • < 1cm = microadenoma
    • > 1cm = macroadenoma
    • General population getting head MRI --> identify 10-38% microadenomas, 0.2% macroadenomas
    • Pituitary adenomas are ALMOST ALWAYS non-malignant
      • Pituitary carcinoma is extremely rare (metastasis to pituitary is also rare)
      • Other causes: craniopharyngiomas, miningiomas, Rathke cleft cysts, amylokd, lymphoma, TB, etc...
      • Lymphocytic hypophysitis is inflammatory lymphocytic infiltration in pregnant or postpartum women.  (can cause transient or permanent pituitary insufficiency) --> treat with sterois


    Approach to Incidentaloma

    • IF CT shows it, must get MRI
    • Three questions
    1. Is it causing mass effect?
      • headaches  (sudden headache = pituitary apoplexy concern)
      • vision loss - needs visual field testing by optho (peripheral loss, bitemporal hemianopsia, or complete blindness)
      • Brain compression (can invade causing seizures, cavernous sinus - III, IV, VI palsy.
    2. Is it secreting excess hormones? (compressing on other secretory cells, causing hyposecretion)
      • Usually non-functioning (but if functioning usually prolactonoma)
    3. Will it grow and cause future problems?


    • Assessment for hormone hypersecretion:
      • Acromegaly
      • Cushing syndrome
      • Prolactinoma.
    • Physical Exam
      • Examine for acromegaly or Cushing Syndrome, etc...
      • Visual field exam (bitemporal hemianopsia)
      • Eye movements:
        • Can invade cavernous sinus (cranial nerve palsy) - diplopia
    • Laboratory Investigations:
      • TSH, T4, Prolactin (prolactinoma most common), LH, FSH, Estradiol
      • AM cortisol levels
      • Serum Prolactin Level
      • Insulin-like growth factor 1 (IGF-1)
    • Management:
      • 1.  Reduce the mass (to prevent mass effect)
      • 2.  Correct hormone hypersecretion
      • 3.  Maintain normal pituitary function
      • Macroadenomas AND Hypersecretory Tumors (NOT Prolactinomas)
        • Surgery is 1st line (Transphenoidal  - very safe)
          • Compilcations (5%): permanent hypopituitarism, significant hemorrhage, optic nerve injury
        • Radiation used as adjuvant tx with residual disease or continued hormone hypersecretion
          • Used as primary for pts who cannot undergo surgery
      • Prolactinomas
        • Medical Therapy
        • Dopamine agonist shrinks prolactinomas
      • Not Secreting
        • Surgery Indications:
          • Visual Field loss
          • Ocular motor palsies
          • Optic chiasm compression
          • Hormone hypersecretion
          • Tumor Growth
          • Loss of pituitary function
        • If asymptomatic (no mass effect and no hormone excess).
          • Repeat MRI in 6mo for macroadenoma and 12mo for microadenoma
            • If no growth --> MRI repeat q1-2y for 3 years and then intermittently thereafter
            • If patient has cancer, exclude metastatic disease



    • Prolactin is under chronic inhibition by dopamine (pulsatile - highest during sleep)
    • Causes:
      • Physiological hyperprolactin conditions:
        • Pregnancy
        • Nipple simulation, coitus
        • Exercise
        • Food intake
      • Neoplastic:
        • Prolactinoma (benign adnoma)
          • Microprolactinomas < 10mm
          • Macroprolactinomas > 10mm
      • Other:
        • Chest well
        • Spinal lesions
        • Drugs (psychotropic agents - LOTS)
        • Thyroid
      • Co-secretion with Growth Hormone Secreting Tumor
    • Workup:
      • Exclude pregnancy!
      • Repeat!
        • prolactin level in a fasting state with no exercise before testing!
        • Prolactin level correlates to prolactinoma size (i.e. small elevations and large mass, not consistent)
      • MRI: All patients with hyperprolactinemia (without a source) should be assessed by MRI
    • Symptoms:
      • Galactorrhea, decreased libido, infertility, headache, osteopenia
      • Women: Oligomenorrhea/Amenorrhea/Hirsutism
      • Men: Erectile Dysfunction
      • Mass Effects (peripheral vision loss, opthalmoplegia)
      • DEXA Scan
    • Treatment:
      • Treat any secondary causes first (tx will normalize prolactin), change causative drugs.
      • 1st Line: Dopamine Agonist is treatment of choice
        • i.e.
          • Drug Pros SIde Effects

            - Daily formulation

            - Cheaper than Cabergoline

            - Nasal Congestion, Upset stomach

            - Dizziness

            - Cabergoline: ass'd with cardiac valve 

              abnormalities (but only in Parkinson's

              pts, on high cabergoline doses)



            - Once or twice weekly

            - More tumor shrinkage

            - More prolactin Lowering

            - Better tolerated

        • Can use even if visual defects
        • Causes rapid drop in prolactin and shrinkage of prolactinomas by 50% (90% of patients)
        • Indications to treat prolactinomas
          • Women: (Estorgen deficiency)
            • Amenorrhea/oligomenorrhea
            • Infertility
            • Galactorrhea
            • Hirsutism    
          • Men:  (testosterone deficiency)
            • Erectile dysfunction
            • Reduced Libido
            • Gynecomastia
          • Headache/Mass Effects, Osteopenia/porosis
      • Women can be treated with OCP to maintain vaginal health and bone mass (if not wishing to conceive)
        • (Too little estrogen to cause prolactin elevation - typically elevates)
      • Can try to withdraw dopamine agonist if prolactin stable >2yrs, and no visible tumor on MRI.


    • Surgery
      • Considered if failed medical mgmt or unresponsive to dopamine agonist. 
      • Consider surgery for cystic prolactinomas (respond poorly to medical therapy)
      • High remission rates (80% for micro, and 40% for macro)
      • Radiation therapy if macroprolactinomas don't respond to medical/surgery treatment.
    • Pregnancy
      • Pituitary gland increases in size during pregnancy, so does prolactinoma.
        • Seen q2-3mo while pergnant
      • Prolactin levels --> useless in pregnancy
      • Dopamine agonists safe in pregnancy (bromocritpine more evidence)
      • Stop drug after conception (except if hx of optic chiasm compression w/ visual field compromize)
        • Re-institute once done nursing
      • Visual field testing required frequently (no need MRI), (q2-3mo??)



    • Characterized by growth hormone hypesecretion 
    • Most common: GH secreting adenoma
    • Usually sporatic (can occur with MEN1)
    • Symptoms:
      • In a child (before epiphyseal plate closure) --> exaggerated growth of longbones occurs - gigantism
      • In Adults:
        • Face Features:
          • Frontal bossing, enlarged nose/lips/tongue
          • Pronathism (jaw line forward)
        • Dental: Malocclusion, Icreased spacing between the teeth;
        • MSK: skin tags; arthritis; carpal tunnel syndrome
        • Other: sleep apnea; excess sweating. 
        • ​Metabolic: Type II DM, CV Disease, HTN, HCM, PAD, 2-3 fold increase in premature mortality
    • NOTE: Higher risk of polyps in colon ca. (screening recommended) - all ppl with growth hormone. 
    • Workup:
      • Elevated IGF-1 level  (Growth Hormone level not useful - pulsatile)
        • GH stimulates liver IGF-1 production, is a good marker, levels correlate with symptoms.
      • OGTT can be useful (hyperglycemia suppresses GH levels < 1ng/mL - excludes acromegaly unless hypersecreted)
      • Pituitary MRI - confirm mass (mostly macroadenomas)
    • Treatment:
      • Normalize IGF-1, normalize GH levels, reduce tumor volume, decr. comorbidities.
        • Soft tissue problems resolve, but bony changes persist
        • (DM, glucose control, HTN, CV risk can be reversed)
      • Transphenoidal Hypothesectomy
        • 90% success with microadenomas, 
        • 40% success with macroadenomas
      • Medical Therapy:
        • Aduvant to surgery (if residual tumor outside sella in cavernous sinus - cannot access)
        • Somatostatin Analogues (normalize GH and IGF-1 levels in 40-65% pts)
          • Drugs Notes Side Effects

            Long-Actin Forms:

            monthly injections

            Diarrhea, abdominal bloating, 

            increased risk of cholelithiasis


            - Oral

            - Inexpensive unlike

            somatostatin analogues

            - Works in 30-40% 

            See above

            - 2nd line, as substitution or

              combination with somatostatin

            - Blocks GH

            - Normalizes IGF-1 in 90%

            - Daily or twice-weekly injection


            - Monitor Serial Liver Chemistry

            - Brain MRI (monitor tumor
              growth - described only)

        • Shrinks tumor modestly (not as good as dopamine agonists in prolactinomas!)
        • Radiation Therapy also an option


    Cushing's Disease

    • Cushing's Syndrome caused by excessive production of ACTH by Pituitary Adenoma
    • See Cushing's Syndrome under adrenal disorders


    Clinically Non-Functioning

    • Most common pituitary tumor (no hormone hypersecretion)
    • Often detected later (since few symptoms), as macroadenomas.
    • Symptoms:
      • (Mass effect:)
      • Headache
      • Visual Field Loss
      • Hypopituitarism 
    • Occasionally LH/FSH produced at higher levels --> referred as LH/FSH producing gonadotroph adenomas. 
    • Treatment:
      • Surgery:
        • to decompress local structures
        • Indications for Surgery of Non-Functioning Adenomas (or LH/FSH secreting)

          • Visual Field loss
          • Compression of adjacent structures
          • Headache
          • Hemorrhage (apoplexy)
          • Hypopituitarism
        • Symptoms often improve after surgery
        • Radiation can be used to control resitual tumor post-surgery (2nd line)
      • NOTE: Medical therapy is ineffective in shrinking tumor. 


    TSH-Secreting Adnomas

    • Extremely rare
    • Usually found in hyperthyroidism
    • Primary hyperthyroidism --> TSH is suppressed. 
    • Central Hyperthyroidism --> TSH is not suppressed with high T4 levels
    • MRI to assess for tumor
    • Surgery to treat + somatostatin analogues.  +/- radiation

    Pituitary Apoplexy

    • Acute infarction or hemorrhage into pituitary gland
      • aka "sheehan syndrome" if in the setting of pregnancy
    • In the setting of enlarged pituitary gland --> highly vascular supply
      • In setting of dropping blood pressure --> can get hemorrhagic infarction
    • Symptoms:
      • S/O: Headache, Diplopia, Acute hypopituitarism
      • Pregnancy:
        • Can present with sudden post-delivery hypopituitarism + inability to lactate
    • Treatment
      • Neurosurgical Emergency - need to decompress
      • Acute ACTH deficiency --> need acute steroids!  (HIGH MORTALITY)
      • Eventually replace thyroid, sex, and growth hormones
    • Diagnosed with CT head
    • Often presents with adrenal insufficiency


    Other incidental findings

    • "empty sella" --> too small to visualize, check for hormone deficiency (8am cortisol, TSH, T4).  No need to repeat imaging.

    Hormone Replacement

    • Must replace all hormones normally supplied by pituitary gland
      • Growth Hormone
      • Hydrocortisone
      • Levothyroxin
      • Testosterone
      • Estrogen/Progestin
    • Hormone Deficiency

      Treatment Dosing (please cross-reference!!)



      Levothyroxine 50-200 mg/d; 

      Measure Free T4

      TSH NOT interpretable


      Hydrocortisone, 10-20 mg in AM and 5-10 mg in PM

      or prednisone, 2.5-5 mg in AM and 2.5 mg in PM; adjust clinically

      Stress dosing for hydrocortisone, 50-100 mg IV every 8 hours.

      Adjust Clinically



      Testosterone: 1% gel, 1-2 packets (5-10 g)

      or 1.62% gel, 2-4 pumps (40.5-81 mg) daily;

      transdermal patch, 5 g daily;

      or testosterone enanthate or cypionate, 50-300 mg IM every 1-4 weeks.

      Will need injectable gonadotropins (LH, FSH) or GnRH for spermatogenesis

      (if fertility is desired).





      Cyclic conjugated estrogens (0.3–0.625 mg)

              and medroxyprogesterone acetate (5-10 mg) 

      or low-dose oral contraceptive pills.

      Estrogen patches also available.

      Will need injectable gonadotropins (LH, FSH) if fertility is desired.



      Adults start at 200-300 μg subcutaneously daily and

       increment by 100-200 μg at bimonthly intervals.

       Adjust to maintain IGF-1 levels in the midnormal range.

      Women receiving oral estrogens require higher doses.

      Monitor IGF-1

      to maintain normal levels


      Desmopressin: metered nasal spray, 10-20 μg once or twice daily;

      or tablets, 0.1-0.4 mg every 8-12 h; or injected, 1-2 μg subcutaneously or

      IV, every 6-12 h


    Specific Hormones

    Growth Hormone Deficiency

    • May reflect childhood onset disease or newly-acquired (with other deficiencies)
    • Symptoms:
      • Children: Short stature
      • Adults:  (most common associated with structural problem - supracellar region)
        • Reduced lean muscle mass
        • Increased fat mass
        • Reduced strengths/stamina
        • Reduced bone BMD
        • Increased CV Risk
        • Poor sense of wellbeing
    • Diagnosis:
      • Cannot measure Growth Hormone itself (GH levels very cyclic and pulsatile)
      • Measure IGF-1 (relased from liver)
        • ​Must measure GH reserve --> must do simulation test
        • i.e. Insulin --> Hypoglycemia --> GH release
        • or Glucagon, Arginine or GHRH
    • Treatment:
      • Poor data that demonstrates treatment improves symptoms --> Generally consult endocrinology


    Gonadotropic Deficiency

    • Hypogonadotropic Hypogonadism --> pituitary gland produces less LH + FSH --> Less estrogen/testosterone
    • Symptoms:
      • Women:
        • Amenorrhea
        • Breast Atrophy
        • Vaginal Dryness
        • Diminished Libido
      • Men:
        • Decreased Libido
        • Loss of skeletal muscle
        • Anemia
      • Both:
        • Loss of bone density
    • Causes:
      • Often acquired:
        • dramatic weight loss
        • dietary restriction (anorexia nervosa)
        • stress
        • heavy exercise
        • severe illness
        • Idiopathic
      • Hyperprolactinemia
        • Suppresses GnRH --> Hypogonadotropic Hypogonadism
    • Workup:
      • Must do MRI or CT to r/o structural disease


    ACTH Deficiency

    • Hypocortisolism
    • Primary:
      • HIGH ACTH in presense of low measured cortisol level 
    • Secondary:
      • LOW ACTH in presense of low measured cortisol level 
    • Symptoms:
      • Initially: malaise, nausea, weakness
      • Eventually: Fever, Hypotension, Fatigue
      • Adrenal Crisis: Often most common presentation is due to stressful event causing adrenal insufficiency (i.e. esp if exogenous steroids are used > 2-3 weeks)
      • Primary: elevated ACTH levels
        • Skin hyperpigmentation in primary!!!
        • Hyperkalemia (mineralcorticoids also absent!)
      • Secondary:
        • Symptoms of hypocortisolism (no skin pigmentation)
    • NOTE: In ACTH deficiency, adrenal production of mineralcorticoids and K+ homeostasis are intact.  RAAS controls mineralcorticoids.  (i..e don't have to give mineralcorticoid for someone in secondary adrenal insufficiency)


    TSH Deficiency

    • In central hypothyroidism, low TSH causes reduced T3/T4 secretion.
    • Symptoms:
      • Same as primary hypothyroidism (fatigue, weight gain, cold intolerance, constipation)
    • Workup:
      • Must measure serum T4 level, and TSH to diagnose
      • Low T4 level, and inappropriately low or normal TSH level. 
    • NOTE: Euthyroid sick syndrome also presents with low TSH and low T4, but in context of severe illness or starvation.
    • Treatment:
      • Thyroid level dosing --> Monitor free T4 level to maintain in mid-normal levels. 
      • Cannot use TSH level to adjust dose. 


    Diabetes Insipitus (ADH Deficiency)

    • Deficiency of ADH hormone (aka arginine vasopressin - AVP)
    • Types:
      • Central (ADH not secreted)
      • Peripheral - aka Nephrogenic (ADH not effective)
    • Pathology:
      • Excretion of dilute urine relative to plasma, causing hyperosmolar serum state, causing extreme thirst (polydipsia) + polyuria.
      • If patients have adequate thirst mechanism + have access to water --> Serum Sodium remain normal or high normal --> Still have polyuria + polydipsia
    • Symptoms:
      • Polyuria + Polydipsia
      • Typically patients drink enough water to compensate.
        • If stressor + no access to water or a CNS event that alters thirst threshold (or pregnancy with placental AVPase)
        • --> DI can become clinically apparent.
    • DDx: (rule out following:)
      • Primary polydipsia (Psychiatric)
      • Medications (i.e. phenothiazines causing dry mouth such as chlorpromazine)
      • Anatomic lesions of Thirst receptor (sarcoid, etc..)
      • Osmotic Diuresis (uncontrolled DMII)
      • Post-Obstructive Diuresis (Prostate Diuresis)
      • Hypercalcemia
    • Workup:
      • Rule out other above causes
      • Get Urine osmolality + Serum Osmolality
        • If uOsm < sOsm (dilute urine) --> DI is likely
      • If baseline sNa+ < 136 mEq/L, but uOsm is high, then DI is unlikely.  (this is likely SIADH)
      • Water Deprivation Test: (Done if Baseline sNa+ levels are normal and DI suspected)


        • Differentiates DI from primary polydipsia
        • Measure sNa and sOsm q2h AND urine volume, urine osm, body weight measured q1h
        • Test is finished when either one is true:

                    1.  uOsm > 600 mOsm/L

                    2.  uOsm fails to concentrate for 2 consequtive hours

                    3.  sOsm > 295 mOsm/L

                    4.  sNa > 145

                    5.  Patient lost > 5% of body weight. 

           - If test is finished, DDAVP is given, and measure urine osm q30min x2hrs



           - Healthy person should raise uOsm > 800 mOsm/L (DI patients cannot increase it > 300 mOsm)

          - Central vs. Peripheral:

                - Give DDAVP: if uOsm increases by 50% --> then central DI

                                       If no change --> peripheral DI                                 




        - If any of these parameters are met before the test begins, DO NOT do H2O deprivation test

          Give DDAVP and measure urine volume and Uosm q30min x2hrs.


    • Causes:
      • Familial
      • Acquired:
        • Neoplasms (Craniopharyngeomas, Germinoma, Metastatic Cancer)
        • Trauma (neurosurgery, TBI)
        • Infiltrative (Sacroidosis, Langerhans Cell Histiocytosis)
      • Transient:
        • After pituitary surgery, but rapidly resolves post-procedure
    • Treatment:
      • Desmopressin (DDAVP) administered orally by metered nasal spray or by SC injection.
      • Instruct patients to drink until no longer thirsty  (otherwise can cause water intoxication)
      • If unconscious patient:  Be careful with fluids.  Use body weights, In/Outs monitoring, serum Na, etc..


    • Hemochromatosis:
      • hormonal changes (1st to last)
        • Low LH, Low FSH, Low Testosterone
    • For patients with hyperprolactinemia:
      • Check TSH and T4.  If they have concurrent primary hyperthyroidism, treat hyperthyroidism first with L-thyroxine.
      • Then recheck prolactin levels.
      • Only invenstigate hyperprolactinemia if prolactin levels continue to be elevated after TSH treatment.
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