Hypopituitarism

Hypopituitarism refers to the inadequate production of one or more anterior pituitary hormones as a result of damage to the pituitary gland and/or hypothalamus. These hormones include growth hormone (GH), prolactin, thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle stimulating hormone (FSH), and luteinizing hormone (LH). In some cases, the posterior pituitary hormones (e.g., ADH) may also be affected, which is known as panhypopituitarism. The most common cause of hypopituitarism is compression of the pituitary gland by a non-secretory pituitary macroadenoma. Other common causes include postpartum pituitary necrosis (Sheehan syndrome), traumatic brain injury, hypophysectomy, and/or irradiation of the pituitary gland. Clinical manifestations vary significantly and depend on the specific hormone deficiency, the age of disease onset, the rate at which hypopituitarism develops, and the underlying cause of hypopituitarism: Growth hormone deficiency during childhood presents with growth retardation, while prolactin deficiency manifests as lactation failure among women. Deficiencies of other anterior pituitary hormones, on the other hand, manifest with clinical features of hypogonadotropic hypogonadism, secondary hypothyroidism, and/or secondary adrenal insufficiency. Severe pituitary damage can also result in central diabetes insipidus as a result of ADH deficiency. Diagnosis of hypopituitarism involves measuring specific hormone levels (depending on the underlying hormone deficiency) and cranial imaging (in order to identify damage to the pituitary gland and/or hypothalamus). Treatment of hypopituitarism consists of hormone replacement therapy and treatment of the underlying disorder (e.g., transsphenoidal resection of pituitary adenomas).

• Intrasellar/parasellar masses
  • Nonsecretory pituitary macroadenomas (≥ 10 mm in diameter) are the most common cause of hypopituitarism among adults (∼ 40% of cases).
  • Less common; : internal carotid artery aneurysms, meningiomas, craniopharyngiomas, Rathke's cleft cyst
• Pituitary apoplexy
  • Infarction of the pituitary gland as a result of ischemia and/or hemorrhage.
  • Most commonly occurs in patients with a pre-existing pituitary adenoma
  • Primarily affects the anterior pituitary gland because it receives its blood supply from a relatively low-pressure arterial system and is, therefore, vulnerable to ischemia and infarction.
  • Sheehan syndrome: postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage.
    • During pregnancy, hypertrophy of prolactin-producing regions increases the size of the pituitary gland, making it very sensitive to ischemia.
    • Blood loss during delivery/postpartum hemorrhage → ; hypovolemia → vasospasm of hypophyseal vessels → ischemia of the pituitary gland
• Traumatic brain injury (especially around the skull base)
• Iatrogenic causes (e.g., hypophysectomy, pituitary irradiation)
• Infiltration of the pituitary and/or hypothalamus
  • Hemochromatosis
  • Infections: meningitis, TB
• Empty sella syndrome
• Congenital deficiency of hypothalamic hormones
  • GnRH deficiency (Kallmann syndrome)

References:^{[1][2][3][4][5][6][7]}

• Hypopituitarism becomes symptomatic when more than 80% of pituitary cells are damaged.
  • In most cases, hypopituitarism develops slowly (e.g., adenomas, post-irradiation)
  • Certain cases of hypopituitarism develop rapidly (e.g., pituitary apoplexy).
• Hypopituitarism refers to deficiency of one or more anterior pituitary hormones (see general endocrinology for their physiological effects)
  • GH deficiency → growth retardation (during childhood), ↓ bone density, muscle atrophy, hypercholesterolemia
  • Prolactin deficiency → lactation failure following delivery
  • FSH/LH deficiency → hypogonadotropic hypogonadism (secondary hypogonadism)
  • TSH deficiency → secondary hypothyroidism
  • ACTH deficiency → secondary adrenal insufficiency
• In addition to the aforementioned hormone deficiencies, patients with severe pituitary damage (panhypopituitarism) also present with deficiencies of posterior pituitary hormones:
  • ADH deficiency → central diabetes insipidus
  • Oxytocin deficiency → no effect

References:^[8][9][10]

Symptoms are variable and depend on the specific hormone deficiency, the age of disease onset, the rate at which hypopituitarism develops, and the underlying cause of hypopituitarism.

• GH deficiency
  • During childhood: short stature
  • During adulthood: usually asymptomatic; subtle findings include weight gain, weakness, and depression
• Prolactin deficiency
  • Females: lactation failure following delivery
  • Males: asymptomatic
• FSH/LH deficiency
  • Females: primary amenorrhea (delayed puberty), secondary amenorrhea, irregular menstrual cycles, infertility
  • Males: delayed puberty, loss of libido, infertility, testicular atrophy, loss of facial, axillary and/or pubic hair, gynecomastia
• TSH deficiency: weight gain, cold intolerance, lethargy, constipation, dry skin (see hypothyroidism)
• ACTH deficiency: weight loss, weakness, hypotension, chronic hyponatremia, hypoglycemia (see adrenal insufficiency)
• Central diabetes insipidus: : polyuria, polydipsia
• Intrasellar/parasellar masses (e.g., pituitary macroadenomas, craniopharyngiomas) can present with headache, visual field defects (bitemporal hemianopsia), and/or diplopia.
• Pituitary apoplexy: manifests with acute onset of
  • Severe headache
  • Hypopituitarism
  • Bilateral hemianopia
  • Diplopia (due to damage to CN III)

Pituitary apoplexy, which results in acute hypocortisolism and hypothyroidism, can manifest with severe headache, sudden hypotension, and hypovolemic shock!

References:^[9]

Since the pattern of hormone deficiency may vary, each hormone deficiency must be tested individually.

• GH deficiency
  • ↓ IGF-1 levels (insulin-like growth factor)
  • ↓ GH levels (even after administering arginine and exogenous GHRH)
• Prolactin deficiency: No routine test is available
• Gonadotropin deficiency
  • Males
    • ↓ Or normal LH, which does not increase even after administering exogenous GnRH (GnRH stimulation test)
    • ↓ DHEA, ↓ testosterone (in a serum sample collected between 8 and 10 am)
  • Females: the presence of regular menstrual cycles effectively rules out gonadotropin deficiency; no further diagnostic test is required.
    • ↓ FSH and ↓ LH and do not rise after a GnRH stimulation test
    • ↓ Estradiol
    • Lack of withdrawal bleeding after administering medroxyprogesterone acetate for 10 days (progesterone challenge test)
    • However, withdrawal bleeding occurs after administering an estrogen preparation for 21 days followed by a progesterone preparation for 7 days (estrogen/progesterone challenge test)
• TSH deficiency: ↓ T₃, ↓ T₄, ↓ or normal TSH (see secondary hypothyroidism)
• ACTH deficiency (see secondary adrenal insufficiency)
  • Low cortisol levels (see ACTH stimulation test)
  • ↓ Serum ACTH
• Central diabetes insipidus: low urine osmolality (< 300 mOsmol/L); which persists despite water deprivation; but increases once exogenous desmopressin is administered (see desmopressin test)
• If a pituitary hormone deficiency is identified: perform cranial imaging (preferably MRI) to identify pituitary adenomas

References:^[9][11][12]

Management consists of treating the underlying cause (e.g., transsphenoidal resection in cases of pituitary macroadenomas) and hormone replacement therapy.

• Growth hormone deficiency
  • Children: GH hormone replacement;
  • Adults: GH hormone replacement is usually not required
• TSH deficiency: : administration of levothyroxine (see hypothyroidism)

Patients with TSH deficiency should not be treated with levothyroxine until ACTH deficiency has been ruled out and/or treated because levothyroxine increases the clearance of cortisol and may precipitate an adrenal crisis!

• ACTH deficiency: glucocorticoid; replacement therapy with increased dosage during periods of stress (see adrenal insufficiency)

Immediate treatment with glucocorticoids, without waiting for diagnostic confirmation, is required when acute ACTH deficiency is suspected (e.g., following pituitary apoplexy) to prevent an adrenal crisis!

• Gonadotropin deficiency
  • Males
    • If fertility is desired: exogenous gonadotropins (e.g., hCG) should be administered
    • If fertility is not desired: testosterone replacement therapy
  • Females: estrogen replacement therapy with/without progesterone
• Prolactin deficiency: no treatment is required
• Central diabetes insipidus: desmopressin

In addition to hormone replacement therapy, the underlying cause of hypopituitarism should be treated, e.g., via transsphenoidal resection in the case of pituitary macroadenomas!

References:^[5][13]