Hypopituitarism

Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. The hormones produced from this lobe are growth hormone, follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone, and prolactin. When the posterior lobe (neurohypophysis) is also damaged, loss of antidiuretic hormone and oxytocin occurs. All of these hormones regulate the activities of different organs, and thus the effects of pituitary hypofunction are multisystemic. The diagnosis is made through a combination of clinical findings, hormone levels, provocation tests, and brain imaging. Treatment is hormone replacement and addressing the etiology.

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Overview

Definition

Hypopituitarism is the condition resulting from inadequate production of pituitary hormones:

  • Primary hypopituitarism: disorders of the pituitary gland
  • Secondary hypopituitarism: disorders of the hypothalamus

Epidemiology

  • < 200,000 people affected in the United States
  • Average yearly incidence rate of 4.21 cases per 100,000
  • No difference in incidence between sexes

Etiology

  • Masses/tumors:
    • Pituitary adenoma/tumors (approximately 50% of cases)
    • Rathke’s cleft cyst
    • Meningioma
    • Craniopharyngioma
    • Lymphocytic hypophysitis (infiltration of lymphocytes causing pituitary enlargement)
  • Systemic causes:
    • Sarcoidosis
    • Wegener’s granulomatosis
    • Hemochromatosis
    • Histiocytosis X
    • Amyloidosis
  • Congenital causes:
    • Pituitary dysplasia: hypoplasia/aplasia/ectopic development
    • Kallman syndrome: defective hypothalamic gonadotropin-releasing hormone (GNRH)/GNRH synthesis
    • Prader–Willi syndrome: varying degrees of hypopituitarism with hyperphagia–obesity, hypotonia, mental retardation, and diabetes mellitus
    • Tissue-specific factor mutations
  • Traumatic causes: 
    • Brain injury
    • Surgery
    • Radiotherapy 
  • Infectious causes 
    • Tuberculosis
    • Syphilis
    • Candidiasis
  • Vascular causes:
    • Sheehan’s syndrome: postpartum pituitary necrosis caused by blood loss during childbirth
    • Pituitary apoplexy: sudden hemorrhage of the pituitary gland, often in the presence of a pituitary adenoma
    • Carotid artery aneurysm
    • Subarachnoid hemorrhage
  • Empty sella syndrome (radiologic finding):
    • May result from:
      • Surgically removed pituitary tumor
      • Cerebrospinal fluid flowing through a defect and filling the space
    • Hypopituitarism can arise insidiously owing to the above processes.

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Pathophysiology

Pituitary gland

  • Also called hypophysis
  • Function: stimulation and/or suppression of activity of the major endocrine glands through secretion of hormones
  • Two lobes with own set of secretory products and feedback loops: 
    • Anterior (adenohypophysis):
      • Growth hormone (GH)
      • Luteinizing hormone (LH)
      • Follicle-stimulating hormone (FSH)
      • Prolactin (PRL)
      • Thyroid-stimulating hormone (TSH)
      • Adrenocorticotropic hormone (ACTH)
    • Posterior (neurohypophysis):
      • Antidiuretic hormone (ADH) or vasopressin
      • Oxytocin
  • Decreased function, or hypopituitarism, is most noted with anterior pituitary lobe damage, as it makes up 80% of the gland.

Hypothalamic–pituitary complex:
The image shows the pituitary gland, made up of the anterior and posterior lobes, in relation to the hypothalamus.

Image: “1806 The Hypothalamus-Pituitary Complex” by OpenStax College. License: CC BY 3.0

Loss of pituitary gland function

  • Damage to the pituitary gland → sequential loss of anterior pituitary hormones:
    • Because of vulnerability to pressure, GH-secreting cells (somatotrophs) are affected first → ↓ GH occurs
    • Followed by ↓ LH and FSH (gonadotropins) → ↓ TSH → ↓ ACTH
    • PRL rarely affected (if deficient, suggestive of total anterior pituitary gland failure)
  • General effect: decreased target gland hormone production
Hormones of anterior pituitary: target organs, function, and effects
HormonePituitary cell typeTarget organFunctionDecreased production
ACTHCorticotrophAdrenal cortexStimulates:
  • Cortisol
  • Androgen
  • Aldosterone
Secondary adrenal insufficiency
GHSomatotrophLiver and other tissuesStimulates protein synthesis and overall growth of most cells and tissues
  • Short stature
  • GH deficiency
ProlactinLactotrophMammary glands
  • Secretion of milk
  • Female breast development
Inability to produce milk (hypoprolactinemia)
TSHThyrotrophThyroid glandStimulates the thyroid gland to synthesize and secrete thyroid hormoneHypothyroidism
LHGonadotroph
  • Ovaries
  • Testes
  • Ovulation, estrogen and progesterone synthesis
  • Testosterone production from interstitial Leydig cells
  • Hypogonadism
  • Kallman syndrome
  • Pasaqualini’s syndrome
FSHGonadotroph
  • Ovaries
  • Testes
  • Growth of follicles in ovaries
  • Sperm maturation
  • Hypogonadism
  • Kallman syndrome
Hormones of posterior pituitary: target organs, function, and effects
HormonePituitary cell typeTarget organFunctionDecreased production
ADHSupraoptic nuclei of hypothalamus
  • Kidneys
  • Arterioles
  • Water reabsorption from kidney
  • Increased blood pressure
  • Vasoconstriction
Diabetes insipidus
OxytocinParaventricular nuclei of hypothalamus
  • Breast
  • Uterus
Stimulates:
  • Milk ejection
  • Uterine contraction
Causes few symptoms, given limited effects

Pituitary gland and target organs:
The pituitary hormones help regulate the activity of endocrine glands throughout the body and play an important role in homeostasis.

Image: “Endocrine glands and cells are located throughout the body and play an important role in homeostasis” by Philschatz. License: CC BY 4.0

Clinical Presentation

Hormone deficiencies

Signs and symptoms are dependent on underlying pathology, speed of onset, and severity of hypopituitarism (partial or complete).

  • Anterior pituitary hormone deficiency can be multihormonal or, in some cases, isolated.
    • ↓ Growth hormone (GH deficiency):
      • In adults: lower bone density, muscle atrophy, dyslipidemia, central obesity
      • In children: short stature, growth retardation
    • ↓ LH and FSH (secondary hypogonadism):
      • Women: ovarian hypofunction (amenorrhea, infertility, breast atrophy, ↓ libido)
      • Men: testicular hypofunction (atrophic testes, ↓ libido, ↓ muscle mass)
    • TSH (secondary hypothyroidism):
      • Signs and symptoms: fatigue, dry skin, delayed deep tendon reflexes, constipation, cold intolerance, bradycardia
      • May have fewer symptoms or symptoms similar to those of primary hypothyroidism
      • In children: growth retardation noted
    • ↓ ACTH (secondary adrenal insufficiency):
      • Signs and symptoms: hypoglycemia, anorexia, vomiting, malaise, weight loss, circulatory collapse
      • No salt wasting/hyperkalemia or volume contraction (aldosterone secretion partially independent from the pituitary gland)
      • No hyperpigmentation
    • Prolactin: failure to lactate (cessation of the production of breast milk)
  • Posterior pituitary hormone deficiency:
    • Only ADH deficiency (diabetes insipidus (DI)) manifests clinically.
    • Signs and symptoms: polyuria, polydipsia, hyponatremia, lethargy
    • Symptoms may improve in the setting of ACTH deficiency (↓ ACTH → secretion of inappropriate ADH or SIADH due to cortisol deficiency).
  • Panhypopituitarism: decreased secretion of most or all pituitary hormones

Nonhormonal presenting features

  • Tumors (cause compressive effect on structures):
    • Headache
    • Visual field defects (e.g., bitemporal homonymous hemianopia) and diplopia
  • Sheehan’s syndrome: 
    • Postpartum hemorrhage associated with hypotension
    • Lethargy, anorexia, inability to lactate
  • Pituitary apoplexy:
    • Sudden excruciating headache
    • Diplopia
    • Acute-onset loss of ACTH causes life-threatening hypotension.
  • Genetic diseases and systemic illnesses: Accompanying symptoms depend on the underlying condition or conditions.

Diagnosis

Laboratory tests

ACTH deficiency: 

  • Obtain morning serum cortisol (between 8 and 9 am):
    • Normal: ≥ 18 mcg/dL: sufficient ACTH
    • Low cortisol (≤ 3 mcg/dl) + low serum ACTH: confirms low ACTH
  • If cortisol is indeterminate (4–17 mcg/dl): 
    • Metyrapone test:
      • Logic: Metyrapone blocks conversion of 11-deoxycortisol to cortisol.
      • Oral metyrapone given; 11-deoxycortisol and cortisol levels obtained after 24 hours
      • Intact ACTH reserve would increase 11-deoxycortisol.
      • Low ACTH reserve confirmed if 11-deoxycortisol < 10 mcg/dl and serum cortisol < 7 mcg/dl
    • Cosyntropin stimulation test:
      • Logic: Chronically decreased ACTH leads to adrenal atrophy (low cortisol).
      • Obtain basal ACTH.
      • Administer IM or IV cosyntropin (ACTH).
      • Low cortisol after 30 and 60 minutes indicates adrenal insufficiency.
      • Secondary adrenal insufficiency (↓ ACTH reserve) confirmed if low basal ACTH
    • Insulin-induced hypoglycemia test:
      • Logic: Insulin causes ↓ glucose, which in turn triggers cortisol secretion in normal circumstances.
      • Inject insulin.
      • Glucose, ACTH, and cortisol are measured in intervals.
      • ACTH deficiency confirmed if inadequate ↑ in cortisol parallel to ACTH at the onset of hypoglycemia

GH deficiency: 

  • ↓ Serum insulin-like growth factor-1 (IGF-1) in GH deficiency
  • Provocative tests:
    • GH-releasing hormone (GHRH) +/– arginine test: Inadequate increase in GH confirms GH deficiency.
    • Insulin tolerance test: inadequate increase in glucose in GH deficiency

TSH deficiency: 

  • Obtain free thyroxine (T4) and TSH.
  • Deficiency confirmed in:
    • Low or low-normal free T4 (thyroxine) level
    • Low serum TSH level

LH/FSH deficiency:

  • In men: low testosterone, low LH
  • In women: 
    • Normal menstrual cycle is indicative of intact pituitary–ovarian function.
    • Low/normal FSH/LH and low estradiol suggest pituitary deficiency.

ADH deficiency: 

  • Water deprivation test and vasopressin stimulation test are used to diagnose DI.
    • Urine osmolality does not increase with serum osmolality.
    • When vasopressin is given, urine osmolality increases.
  • Test also used to differentiate psychogenic polydipsia and nephrogenic DI.

Additional tests

  • Vision field tests look for defects caused by optic nerve compression.
  • Metabolic panel (checking electrolytes, glucose)
  • Laboratory tests directed at the underlying system illness
  • Imaging: brain MRI or CT scan to detect pituitary tumors/intracranial pathology

Management

Hormone replacement

  • Adrenal insufficiency: 
    • Hydrocortisone replacement (other corticosteroids may be used)
    • Increased dose needed in stress, illness, or surgery
  • TSH deficiency: 
    • L-thyroxine
    • Thyroxine decreases cortisol and can aggravate cortisol deficiency.
    • Do not administer until ACTH deficiency is treated or ACTH reserve is confirmed.
  • GH deficiency:
    • Daily injections of recombinant human GH preparation (in children)
    • Monitor response and adherence with IGF-1.
  • Gonadotropin deficiency (no desire for fertility):
    • Female: estradiol + progestin (in postmenopausal women, give only if needed for hot flashes)
    • Male: testosterone replacement
  • Gonadotropin deficiency (desires fertility):
    • Female: ovulation induction with gonadotropins
    • Male: hCG injections
  • ADH deficiency:
    • Desmopressin
    • Low-solute diet, thiazide diuretic

Specific treatments

  • Adrenal crisis:
    • Life-threatening emergency: more common in primary adrenal insufficiency
    • May occur in secondary adrenal insufficiency in settings such as:
      • Pituitary infarction
      • Surgery involving the pituitary gland
    • Not associated with decreased volume, but there is decline in vascular tone → hypotension
    • Do not delay treatment!
    • Give IV fluids and IV hydrocortisone.
  • Pituitary apoplexy: surgical decompression
  • Pituitary macroadenoma: transsphenoidal surgery for large lesions causing neurologic symptoms
  • Antibiotics for infections
  • Etiology-directed treatments for systemic conditions

Differential Diagnosis

  • Primary adrenal insufficiency: inadequate production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens) caused by damage in the adrenal gland. Suspect this condition, also called Addison’s disease, in hyponatremic patients with hyperkalemia (caused by reduced aldosterone). In secondary adrenal insufficiency, aldosterone is unaffected.
  • Hyponatremia: A serum sodium concentration of < 135 mEq/L can be due to other endocrine disorders, such as hypocortisolism or hypoaldosteronism caused by adrenal insufficiency. Diagnosis can be made via ACTH or corticotropin-releasing hormone (CRH) stimulation tests.
  • Hypothyroidism: Secondary causes of hypothyroidism, such as hypopituitarism, can be differentiated from primary thyroid disorders via hormone tests. Low TSH levels are seen in secondary hypothyroidism.
  • DI: condition resulting from decreased secretion of ADH. Patients present with polyuria, thirst, and fatigue. Water deprivation test differentiates DI from primary polydipsia. To determine central versus nephrogenic DI, administer desmopressin; a rise in urine osmolality occurs if central DI (possibly caused by hypopituitarism) is present.
  • Primary hypogonadism: In males, this refers to a decrease in function of the testes (sperm and testosterone production). In females, ovarian insufficiency occurs and manifests as menstrual irregularities. Diagnosis is made by determining levels of pituitary and sex hormones. In males, semen analysis is also performed. Low sex hormones with above normal LH and FSH indicate primary organ failure. 
  • GH deficiency: A decrease in GH can be congenital or acquired. In the pediatric population, presentation can range from microgenitalia to short stature. In adults, less energy, with decreased bone density and reduced lean body mass, are noted. Treatment (growth hormone injections) is necessary for children. In adults, hormone treatment is not routine.
  • Hypoprolactinemia: rarely occurs as an isolated disease. This condition most often occurs because of general anterior pituitary hormone dysfunction. Patients present with inadequate lactation. If milk production is absent, bottle-feeding infants is necessary.
  • Kallmann syndrome: a condition characterized by a deficient release of GnRH by the hypothalamus, leading to secondary hypogonadism with low levels of LH, FSH, and GNRH. This can be differentiated from primary hypogonadism, which presents with high levels of GNRH. Pituitary causes of hypogonadism are also present with low levels of gonadotropin.

References

  1. Chapman, I. (2019). Generalized hypopituitarism. Merck Manuals. Retrieved February 5, 2021, from https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/pituitary-disorders/generalized-hypopituitarism
  2. Chung, T., Koch, C., Monson, J. (2018). Hypopituitarism. Endotext. Retrieved February 6, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK278989/
  3. Corenblum, B., Mulinda, J. (2020). Hypopituitarism. Medscape. Retrieved January 26, 2021, from https://emedicine.medscape.com/article/122287-overview#a5
  4. Kim, S. (2015). Diagnosis and Treatment of Hypopituitarism. Endocrinol Metab (Seoul). 30(4): 443–455. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722397/#
  5. Melmed S., Jameson J. (2018). Hypopituitarism. Jameson J, Fauci A. S., Kasper D. L., Hauser S. L., Longo D. L., Loscalzo J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.
  6. Snyder, P. (2019). Causes of hypopituitarism. UpToDate. Retrieved February 6, 2021, from https://www.uptodate.com/contents/causes-of-hypopituitarism
  7. Snyder, P. (2020). Clinical manifestations of hypopituitarism. UpToDate. Retrieved February 6, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-hypopituitarism
  8. Snyder, P. (2020). Diagnostic testing for hypopituitarism. UpToDate. Retrieved February 6, 2021, from https://www.uptodate.com/contents/diagnostic-testing-for-hypopituitarism

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