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A. Introduction

  1. Occurrance
    1. Incidence ~4/100,000 per year overall
    2. Prevalence ~45/100,000; ~25,000 in USA overrall
    3. Primarily due to pituitary tumors
  2. General Causes
    1. Pituitary Failure
    2. Hypothalamic Failure
    3. Post-radiation for brain tumors
    4. Genetic (familial) mutation syndromes
  3. Anterior Pituitary Hormones
    1. Growth Hormone (GH) - stimulated by GHRH and Ghrelin, inhibited by somatostatin
    2. Prolactin - stimulated by TRH, inhibited by dopaminergic neurons from hypothalamus
    3. Corticotropin (ACTH) - pro-opiomelanocortin processed to ACTH + MSH + Endorphin
    4. Thyrotropin (TSH) - stimulated by TRH from hypothalamus
    5. Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) - stimulated by GnRH
  4. Posterior Pituitary Hormones
    1. Less affected in hypopituitarism due to pure pituitary failure
    2. Synthesized in hypothalamus and transported down to posterior pituitary
    3. Vasopressin (anti-diuretic hormone, ADH) - reduces diuresis, increases blood pressure
    4. Oxytocin - responsible for milk "let-down"
  5. Hypopituitarism is associated with ~1.8 fold increased risk of premature death [6]

B. Causes

  1. General Classes
    1. Brain Damage (probably slightly more common than pituitary tumors) [1,3]
    2. Pituitary Tumors
    3. Non-Pituitary Tumors
    4. Infections
    5. Infarction (pituitary apoplexy)
    6. Autoimmune Disorders
  2. Brain Damage [3]
    1. Traumatic brain injury (TBI)
    2. Subarachnoid hemorrhage (SAH)
    3. Iatrogenic: Neurosurgery, Brain Irradiation
    4. Stroke
  3. Pituitary Tumor
    1. Microadenoma versus Macroadenoma (>10mm)
    2. Specific Cell Type involved (secretory vs. non-secretory)
    3. Craniopharyngioma
    4. Metastatic Disease (primary tumor is always evident): lung, breast most commonly [5]
    5. Tathke's Pouch Cyst
    6. Most common tumors secrete prolactin, leading to hyperprolactinemia (see above)
  4. Non-Pituitary Tumors
    1. Parasellar Tumor: Meningioma
    2. Hypothalamic Tumor
  5. Infection
    1. Tuberculosis
    2. Mycoses
    3. Abscess
    4. Hypophysitis
    5. Meningitis
    6. Encephalitis
  6. Pituitary Apoplexy [4,13]
    1. Hemorrhage into pituitary tumor - anti-coagulation, idiopathic, diabetes, others
    2. Postpartum Hemorrhage (Sheehan's Syndrome) - usually with hypovolemia
    3. Pituitary hemorrhage into normal gland due to ischemia is much rarer
    4. May present with sudden headahce, vomiting, visual impairment, ophthalmoplegia
    5. Altered consciousness may also occur
    6. Meningismus / stiff neck is not uncommon
    7. This is a medical emergency due to pan-hypopituitarism
    8. Hydrocortisone is given first, then thyroxine
  7. Infiltrative Diseases
    1. Granulomatous: Sarcoidosis, , Wegener's Granulomatosis
    2. Histiocytosis
    3. Metastatic Disease
    4. Hemochromatosis
  8. Genetic
    1. Familial disease due to mutations in Pit-1 or Prop-1 genes
    2. These genes are transcription factors which control anterior pituitary development
    3. Loss of Pit-1 or Prop-1 function leads to TSH, GH, and prolactin deficiencies only
    4. Gonadotroph and corticotroph secreting cells are not affected
    5. These syndromes account for <5% of cases of hypopituitarism
  9. Other
    1. Empty Sella - crowded pituitary fossa due to arachnoid herniation through incomplete diaphragm
    2. Internal carotid artery aneurysm

C. Presentation

  1. Adrenal Dysfunction and Addisonian Crisis
    1. Nausea, vomiting, fatigue
    2. Hypotension (orthostatic initially)
    3. Hyponatremia and hyperkalemia
    4. Weight loss
    5. Constipation
    6. Growth retardation
    7. Bradycardia
    8. May mask central diabetes insipidus
  2. Severe Hypothyroidism
    1. Constipation
    2. Severe fatigue
    3. Weight gain
    4. Cold intolerance
    5. Hypertension
    6. Hyperthyroidism can severely exacerbate adrenal insufficiency
  3. Growth Hormone (GH) Deficiency [12]
    1. Common in hypothalmopituitary disease
    2. Changes in body composition most noticable in adults with GH deficiency
    3. Increased fat mass, reduced lean muscle mass and strength
    4. Impaired psychological well-being
    5. Reduced bone-mineral density
    6. Altered renal and cardiac function
    7. Altered lipoprotein and carbohydrate metabolism
    8. GH deficiency may also be manifest in abnormal IGF-1 or its acid labile subunit [8]
  4. Non-Specific Systemic Complaints
    1. Fatigue, malaise
    2. Temperature dysregulation
    3. Intermittant headaches
    4. Weakness
    5. Oligomenorrhea
  5. Estrogen Deficiency [10]
    1. Amenorrhea
    2. Oligomenorrhea
    3. Infertility
    4. Loss of libido
    5. Osteoporosis (long term)
    6. Premature atherosclerosis (long term)
  6. Androgen Deficiency
    1. Loss of libido
    2. Impaired sexual function
    3. Decreased muscle mass and strength
    4. Osteoporosis
    5. Reduced hair growth (androgen dependent skin functions)
    6. Anemia
  7. Diabetes Insipidus
    1. Common finding after pitutiary surgery
    2. Temporary or permanent shut-down of antidiuretic hormone (ADH) production/release
    3. May present as mild stunning with transient DI to permanant ADH deficiency
    4. After death of ADH-containing axons, ADH may be released causing temporary ADH excess
    5. This ADH excess (SIADH) is then followed by permanent DI
    6. Hypovolemia, hypernatremia, and/or hypotension may occur
  8. Pituitary Mass Lesion
    1. Headache - may be severe [4]
    2. Photophobia
    3. Cranial Nerve III problems - double vision
    4. May mimic aseptic meningitis
    5. About 10% of asymptomatic adults have pituiatry masses by MRI
    6. Pituitary rupture and hemorrhage ("apoplexy") have similar symptoms with fever [13,14]
    7. Consider pituitary apoplexy with fever, headache, stiff neck [13]
    8. Similar syndrome may occur following surgery to remove pitutiary tumors
    9. Most macroadenomas secrete prolactin
    10. Hyperprolactinemia may be initial presentation (see below)
  9. Hyperprolactinemia
    1. Amenorrhea
    2. Galactorrhea
    3. Infertility
  10. Frank hypothermia may also occur (damage to thermal set-point control center) [5]
  11. Premature mortality related to cardiovascular, respiratory, and cerebrovascular disease
  12. Risk Factors for Premature Mortality [6]
    1. Craniopharyngioma (most important)
    2. Age at diagnosis >40 years
    3. Female sex
    4. Untreated gonadotropin deficiency

D. Evaluation

  1. Patients with one or more anterior pituitary deficiencies should be fully evaluated
  2. Hormone Levels for various systems are analyzed
  3. Prolactin Level
    1. Hyperprolactinemia and macroadenoma is most common presentation of hypopituitarism
    2. Amenorrhea, Galactorrhea, and/or Infertility occur
    3. Prolactin levels should be obtained in ALL patients with hypopituitarism
  4. Adrenal Function
    1. Document AM serum cortisol leves: normal level is >5µg/dL
    2. Level <3µg/dL is diagnostic of adrenal insufficiency
    3. Stimulation test should then be performed (to assess response of adrenals)
    4. Give 25µg Cortrosyn or 250µg Cosyntropin, measuring cortisol after stimulation
    5. Metyrapone rapid test is well tolerated and
  5. Thyroid Function
    1. In suspected pituitary insufficiency, free T4 concentrations are the gold standard
    2. TSH (thyrotropin) levels are not sensitive or specific for this disease
    3. Patients typically have low T4 and FTI levels and low TSH levels
    4. Serum T3 levels are not helpful either (often in normal range with very low Free T4)
    5. TRH levels are generally elevated with pituitary insufficiency
    6. TRH levels are abnormally low in hypothalamic dysfunction
  6. Gonadotrophins in Women
    1. Gonadotrophin deficiency manifests as menstrual irregularities in premenopausal women
    2. Low serum estradiol with low or normal FSH is sufficient for the diagnosis
    3. Because hyperprolactinemia can cause menstrual irregularities, it must be ruled out
    4. Elevated testosterone levels in women can be indicative of polycystic ovary syndrome
    5. In general, prolactin, FSH (±LH), and estrodiol levels should always be checked
    6. Testosterone levels may be checked in non-menstruating women
  7. Gonadotrophins in Men
    1. Low serum testosterone and low or normal FSH is diagnostic in men
    2. Sex hormone binding globulin levels should be determined to evaluate free testosterone
    3. Hyperprolactinemia should be excluded
  8. Growth Hormone (GH)
    1. GH deficiency in absence of other anterior pituitary insuffiencies is uncommon
    2. Lack of GH production must be distinguished from lack of response to GH
    3. Specific GH insensitivity syndromes described well due to genetic mutations
    4. GH insensitivity usually due to low levels of GH binding protein (GH receptor N terminus), less commonly by STAT5b mutation [15]
    5. Direct measure of baeline GH levels is not reliable
    6. GH stimulates Insulin Like Growth Factor I (IGF-1) production
    7. Thus, IGF-1 levels usually helpful to determine if GH is being made and signal received
    8. Low IGF-1 levels are strongly suggestive of reduced GH production or insensitivity
    9. To document true GH deficiency, a stimulation test using either insulin, GHRH with arginine, or pyridostigmine is performed
    10. Normal persons increase peak serum GH concentrations to >3-5µg/L
    11. Combined GHRH and GHRP-6 is probably best method for evaluating inducibility of GH secretion in adults with possible GH deficiency [12]
  9. ADH (Vasopressin)
    1. ADH is synthesized in hypothalamus then transported to the intermediate stalk
    2. Stored in posterior pituitary
    3. ADH deficiency is uncommonly part of hypopituitarism
    4. However, it does occur in some cases of pituitary trauma
    5. Evaluation usually with ADH levels and water deprivation test
    6. Replacement therapy is low dose desmopressin is effective
  10. Other Laboratory Abnormalities
    1. Diabetes mellitus
    2. Dyslipidemia
    3. Cardiovascular complications
    4. Osteoporosis
  11. CT and MRI Scanning - evaluation of pituitary anatomy (MRI preferred)
  12. Lumbar puncture may be useful for evaluating apoplexy, ruling out infection

E. Treatment

  1. Treatment as for individual hormone deficiencies
  2. Order of initiation of replacement therapy is important
    1. Glucocorticoids must be replaced first
    2. Thyroid hormone replacement should always FOLLOW glucocorticoids
    3. Gonadotropins and/or sex steroids may be replaced next
    4. Growth hormone replacement
    5. When present, vasopressin deficiency should be replaced after glucocorticoids
  3. Glucocorticoid Replacement
    1. Oral hydrocortisone 10-25mg per day (divided 15/10 or preferably 10/10/5)
    2. Higher replacement doses are not required and will lead to deleterious chronic effects
    3. Additional mineralocorticoids generally not needed
    4. During severe stress, 100-150mg hydrocortisone IV (divided q8-12 hours) must be given
    5. Stress includes myocardial infarctions, infections, stroke, trauma, burns, others
  4. Thyroid Replacement
    1. Thyroid replacement is given AFTER glucocorticoids or thyrotoxicosis occurs
    2. Although recombinant TSH (thyrotropin) is available, thyroxin (Synthroid®) is used
    3. For >60 years dose is initially 1.1µg/kg body weight
    4. For <60 years, dose is initially 1.3µg/kg body weight
    5. Follow free T4 levels
    6. TSH levels are not helpful in patients with hypopituitarism or hypothalamic disease
  5. Gonadotropins and Sex Hormones
    1. Premenopause: estrogen + progesterone, cyclical; consider oral contraceptive
    2. Menopause: hormone replacement therapy (ERT/HRT) is generally recommended
    3. Untreated gonadotropin deficiency contributes to excess mortality in hypopituitarism [6]
  6. Androgen Replacement Therapy [7]
    1. Long acting Testosterone esters (given IM) are typically used
    2. Usually testosterone enanthate, 200-300mg IM q 2-4 week OR
    3. Testosterone proprionate 200mg IM q2-3 weeks OR
    4. Testosterone undecanoate 1000mg IM q12 weeks OR
    5. Testosterone buccal pellet 30mg bid OR
    6. Oral testosterone undecanoate 40mg po bid-qid OR
    7. Testosterone patches (transdermal) changed daily (4-6mg/day) OR
    8. Testosterone gel 25-50mg/day
    9. Adjust dose to normal testosterone concentrations
    10. Measure prostate size, PSA, and hematocrit (HCT)
    11. Measure serum FSH and LH if fertility concerning
  7. Growth Hormone Replacement [16]
    1. Recombinant GH (rGH) may be beneficial in persons with hypopituitarism
    2. Begin deficient patients at 20-40µg/kg/day and increase over several weeks
    3. Standard dose for children 25-50µg/kg/day
    4. Standard dose is 40-80µg/kg/day for replacement therapy in adults
    5. Low dose rGH (10µg/kg/d) Increased bone mineral density in lumbar spine
    6. Dose of rGH is adjusted by following serum IGF-1 levels
    7. Significant improvement in markers of bone turnover
    8. Body fat was reduced as well and lean body mass increased
    9. Recombinant GH releasing hormone (GHRH) is also available [9]
    10. GHRH is about 55% of the price of most rGH, but may be less effective [9]
    11. rGH reduces levels of inflammatory cardiovascular risk markers and central fat in men with GH deficiency [11]
    12. rGH increases lipoprotein(a) and glucose levels without affecting other lipid levels [11]
  8. ADH Replacement [1]
    1. Desmopressin oral (0.3-1.2mg/day) OR
    2. Desmopressin intranasal (10-40µg/day) in 1-4 doses per day'
    3. Adjust to normalization of fluid intake

References

  1. Schneider HJ, Aimaretti G, Kreischmann-Andermahr I, et al. 2007. Lancet. 369(9571):1461 abstract
  2. Lamberts SWJ, de Herder WW, van der Lely AJ. 1998. Lancet. 352(9122):127
  3. Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, et al. 2007. JAMA. 298(12):1429 abstract
  4. Embil JM, Kramer M, Kinnear S, Light RB. 1997. Lancet. 350:182 abstract
  5. Grinspoon SK and Hedley-White ET. 2001. NEJM. 345(20):1483 (Case Record)
  6. Tomlinson JW, Holden N, Hills RK et al. 2001. Lancet. 357(9254):425 abstract
  7. Bagatell CJ and Bremner WJ. 1996. NEJM. 334(9):707
  8. Domene HM, Bengolea SV, Martinez AS, et al. 2004. NEJM. 350(6):570 abstract
  9. Growth Hormone Releasing Factor for Growth Hormone Deficiency. 1999. Med Let. 41(1043):2 abstract
  10. Adashi EY and Hennebold JD. 1999. NEJM. 340(9):709 abstract
  11. Sesmilo G, Biller BMK, Llevadot J, et al. 2000. Ann Intern Med. 133(2):110
  12. Popovic V, Leal A, Micic D, et al. 2000. Lancet. 356(9236):1137 abstract
  13. Ma RC, Tsang MW, Ozaki R, et al. 2004. Lancet. 363(9424):1686 (Case Report)
  14. Kaiser UB and Hedley-Whyte ET. 2001. NEJM. 344(20):1536 (Case Record)
  15. Kofoed EM, Hwa V, Little B, et al. 2003. NEJM. 349(12):1139 abstract
  16. Baum HBA, Biller BMK, Finkelstein JS, et al. 1996. Ann Intern Med. 125(11):883