Deficiency of multiple pituitary hormones
Basics Risk Factors Genetics
- Congenital forms affect both sexes equally and are diagnosed at a young age.
- The incidence of secondary forms depends on the underlying cause.
There are rare cases of autosomal recessive, autosomal dominant, and X-linked forms.
Pathology is based on specific deficiency:
- Growth hormone (GH): Hypoglycemia in newborns and poor growth in other patients
- Adrenocorticotropic hormone: Hypocortisolism
- Thyroid-stimulating hormone (TSH): Hypothyroidism
- Luteinizing hormone (LH)/follicle-stimulating hormone (FSH): Hypogonadism
- Antidiuretic hormone: Diabetes insipidus
- Prolactin: Hyperprolactinemia
- Idiopathic (some may be due to hypophysitis)
- Absence of the pituitary (empty sella syndrome)
- Genetic disorders due to mutations in genes or transcription factors
- Pituitary malformations (ectopic posterior pituitary, hypoplastic infundibular stalk, hypoplastic pituitary)
- Familial panhypopituitarism
- Birth trauma or perinatal insult
- Surgical resection of the gland or damage to the stalk
- Traumatic brain injury
- Child abuse
- Iron deposition secondary to chronic transfusion therapy (e.g., β-thalassemia)
- Viral encephalitis
- Bacterial or fungal infection
- Pituitary infarction
- Pituitary aneurysm
- Cranial irradiation
- Primitive neuroectodermal tumor (medulloblastoma)
- Midline defects (e.g., cleft lip/palate, hypotelorism, single central maxillary incisor)
- Septo-optic dysplasia (de Morsier syndrome)
Signs and Symptoms
- Birth history:
- Documented or symptoms of hypoglycemia, which include poor feeding, lethargy, irritability, or seizures
- Hypoglycemia may be secondary to hyperinsulinism (HI), but HI babies are typically large for gestational age.
- Hypopituitary babies are not large.
- Midline defects are associated with hypopituitarism and not HI.
- Complications during pregnancy or delivery:
- Birth trauma may be associated with pituitary injury.
- Breech delivery or vacuum extraction has been associated.
- Birth weight: Hypopituitary infants are usually normal or small for gestational age, in contrast to hyperinsulinemic infants, who are typically large.
- History of surgeries and previous diseases: Congenital hypopituitarism is often associated with midline facial defects (e.g., single central incisor, bifid uvula, or cleft palate), which require repair.
- Growth pattern: Plot previous heights and look for growth pattern. GH deficiency usually manifests as poor linear growth by the end of the first year of life.
- Delayed puberty:
- Children with delayed puberty show further growth failure in adolescence.
- Sense of smell should be assessed to rule out Kallmann syndrome (isolated central hypogonadism and anosmia).
- Increased thirst and urination: Children with hypothalamic disorders may present with symptoms of diabetes insipidus.
- Complaints of headache: Headache can be a symptom of a brain tumor.
- Focal neurologic symptoms are highly suggestive of CNS pathology.
- Height and weight:
- Patients with panhypopituitarism have normal size in the newborn period.
- Patients with HI are typically large for gestational age.
- Prolonged conjugated hyperbilirubinemia:
- May be 1st sign of hypothyroidism with or without hypopituitarism
- Some state newborn screens will not detect central hypothyroidism.
- Hypopituitarism can lead to neonatal cholestasis.
- Micropenis in male newborns: Neonatal penis should be ≥2.5 cm in length; micropenis suggests gonadotropin and/or GH deficiency
Physical examination tricks:
- Penile and testicular size: Measure stretched phallic length (from pubic ramus to glans) with patient lying supine and phallus at 90° to the body; use Prader beads to assess testicular volume.
- Midline defects: Palpate for submucosal cleft palate, look for central incisor.
- Visual field testing: Visual field defects suggest a brain tumor.
- Liver function tests: Typically elevated liver enzymes in the newborn period
- Thyroid function tests including free thyroxine (T4): TSH may be normal, but free T4 will be low.
- Thyrotropin-releasing hormone stimulation test: Delayed, normal, or exaggerated TSH response is consistent with a hypothalamic lesion.
- Serum insulinlike growth factor-I (IGF-I) and insulinlike growth factor binding protein-3 (IGFBP-3): May be low, but normal growth factors do not exclude GH deficiency in children with brain tumors. IGF-1 may be low secondary to poor nutritional status.
- Free T4 by equilibrium dialysis: Must measure, not calculate, the free T4 concentration in serum
- GH stimulation tests: Should be performed by a pediatric endocrinologist
- Cortrosyn stimulation test: More helpful in the diagnosis of primary adrenal insufficiency than secondary (adrenocorticotropic hormone) or tertiary (corticotropin-releasing hormone) deficiency
- Metyrapone or corticotropin-releasing hormone stimulation test:
- Definitive tests for adrenocorticotropic hormone or corticotropin-releasing hormone deficiency
- Metyrapone not currently available in the US
- Must be performed by a pediatric endocrinologist
- Estradiol, testosterone, ultrasensitive LH and FSH: Delayed puberty if no breast development by 13 years in girls, and no testicular enlargement by 14 years in boys
- Water deprivation test:
- Definitive test for antidiuretic hormone deficiency (diabetes insipidus)
- Should be performed by a pediatric endocrinologist
Comments on testing:
- Measurement of water intake and urine output over 24 hours at home can help diagnosis of diabetes insipidus.
- Baseline serum tests can all be done in a nonfasting state.
- Stimulation tests need to be performed by a pediatric endocrinologist.
- Bone age: Typically significantly delayed in GH deficiency or hypothyroidism
- MRI with contrast of brain with fine cuts through the pituitary hypothalamus:
- Look for tumors but also size of pituitary, infundibulum, and presence of normal bright spot in posterior pituitary.
- Absence of the bright spot is highly associated with central diabetes insipidus.
- Ectopic pituitary consistent with GH deficiency and other anterior pituitary deficiencies
- If adrenocorticotropic hormone deficient, stress dosing of glucocorticoids is necessary.
- A patient with diabetes insipidus who does not have an infact thirst mechanism and access to free water is at high risk for acute hypernatremia.
- HI in newborns
- Isolated hormone deficiency, such as GH
- Constitutional growth delay
- Recombinant human GH (rhGH) by SC injection daily: 0.3 mg/kg/wk
- Desmopressin acetate (DDAVP): Available in oral and intranasal formulations. Dose is variable.
- Estrogen/Testosterone: Initiated at time of puberty at low doses and slowly increased over 1–2 years to mimic endogenous secretion of sex steroids.
- Estrogen given as oral form to girls while testosterone given as injection to boys every month
- Levo-thyroxine (Levo-T) PO: 25–200 levo-T4 mcg daily, based on weight, age, and free T4 levels
- TSH levels will not be useful in monitoring therapy, even after treatment is initiated.
- Replacement doses if needed: 8–15 mg/m2/day PO, divided q8h (or t.i.d.)
- In stress circumstances such as fever or illness, dose increased to 25–100 mg/m2/day PO
- For surgery, major illness, vomiting: Loading dose of 50–100 mg/m2 IM or IV followed by 50–100 mg/m2 divided q4h; oral stress doses should be divided q8h.
- To calculate hydrocortisone dose, estimate body surface area (BSA) using a nomogram or the following formula: BSA (m2) = square root of (height [cm] × weight [kg]/3600)
- Long-term therapy: Monitored by a pediatric endocrinologist
- In children and adolescents: Until growth velocity drops to 2.5 cm/yr; once puberty is complete
- GH-deficient adults may benefit from lifelong rhGH therapy because of the impact of GH on body composition, lipid profile, and cardiac function.
- Patient should again undergo GH provocative testing off rhGH therapy to determine if adult treatment is necessary.
- DDAVP: For life as needed to control symptoms of polyuria/polydipsia
- Acute hypernatremia may be managed with DDAVP, intravenous vasopressin, or fluids alone.
- Sex steroids: Around age 12, may be continued for lifetime
- Levo-thyroxine for life
- Replacement dose based on individual’s need
- Stress dose coverage for life
- Possible conflicts with other treatments:
- There is a theoretical risk that GH might stimulate tumor growth because of its mitogenic effect. Current data argue against GH as a tumor stimulant.
- GH: Immediate resolution of hypoglycemia, if present, and improved growth velocity within 3–6 months
- T4 levels should normalize within 4–6 weeks.
- Endocrine prognosis for congenital forms is excellent.
- Prognosis for secondary forms depends on the primary disease.
- Hypoglycemia in the newborn period
- Short stature
- Adrenal crisis
- rhGH therapy is associated with idiopathic intracranial hypertension (pseudotumor cerebri), which typically improves whether or not medication is stopped.
- rhGH deficiency/therapy is associated with slipped capital femoral epiphysis. Carefully evaluate any limp or knee or hip pain in patients on rhGH therapy. Slipped capital femoral epiphysis mandates orthopedic consultation.
- GH is a mitogenic factor, so there has been a theoretical potential for increasing the incidence of leukemia. Clinical studies have not confirmed this hypothesis.
- The family and the patient must understand the importance of taking stress doses of steroid appropriately (e.g., with surgery, vomiting, or febrile illnesses).
- You must consider the diagnosis of panhypopituitarism in patients with hypoglycemic seizures.
- Normal children can fail to respond to GH provocative testing.
- Ordering a TSH level is generally not helpful when evaluating pituitary/hypothalamic causes of hypothyroidism. The unbound free T4 level (by equilibrium dialysis) is the most useful test both to establish the diagnosis and to monitor L-thyroxine replacement therapy.
- Q: When do I give the stress dose of steroid and for how long?
- A: Whenever the patient has fever, vomiting, serious illness, or surgery. Continue until 24 hours after stress resolves (e.g., the day after fever breaks or vomiting stops).
- Q: What are the chances of cretinism if hypopituitarism is congenital?
- A: Minimal, if medication is taken properly.
- De Vries L, Lazar L, Phillip M. Craniopharyngioma: Presentation and endocrine sequelae in 36 children. J Endocr Metab. 2003;16:703–710.
- Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clin Endocrinol (Oxf). 2006;64(2):115–121. [PMID:16430706]
- Maghnie M. Diabetes insipidus. Horm Res. 2003;59(Suppl 1):42–54. [PMID:12566720]
- McGauley G, Cuneo R, Salomon F Growth hormone deficiency and quality of life. Horm Res. 1996;45:34–37. [PMID:8742116]
- Parks JS, Brown MR, Hurley DL Heritable disorders of pituitary development. J Clin Endocrinol Metab. 1999;84:4362–4370. [PMID:10599689]
- Reynaud R, Gueydan M, Saveanu A Genetic screening of combined pituitary hormone deficiency: Experience in 195 patients. J Clin Endocrinol Metab. 2006;91(9):3329–3336. [PMID:16735499]
- Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. 1995;31:1113–1121. [PMID:7713777]
Vaneeta Bamba, MDCraig A. Alter, MD (4th Edition)
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