Not surprisingly, high rates of partial or complete hypopituitarism are seen in patients following surgical removal of pituitary tumors or nearby neoplasms (e.g. craniopharyngiomas). Both surgery and radiotherapy for non-pituitary brain tumors are also major risk factors for development of hypopituitarism, occurring in up to 38% and 41% of patients, respectively.6 The strongest predictors of hormone failure are higher radiation doses, proximity to the pituitary-hypothalamus, and longer time interval after completion of radiotherapy. Within 10 years after a median dose of 5000 rad (50Gy) directed at the skull base, nasopharynx, or cranium, up to three-fourths of patients will develop some degree of pituitary insufficiency. Later onset of hormone failure usually reflects hypothalamic injury, whereas higher irradiation doses can lead to earlier onset pituitary damage.5
Not all hormone-secreting cells of the hypothalamus or pituitary are equally susceptible to injury; there is a characteristic sequence of hormonal failure. The typical order of hormone deficiency from pituitary compression or destruction is as follows: growth hormone (GH) > follicle-stimulating hormone (FSH) > luteinizing hormone (LH) > TSH > adrenocorticotropic hormone (ACTH) > vasopressin. A similar pattern is seen following brain irradiation: GH > FSH and LH > ACTH > TSH. A recent systematic review of 18 studies with 813 patients receiving cranial radiotherapy for non-pituitary tumors found pituitary dysfunction was 45% for GH deficiency, compared to 22% for ACTH deficiency.7
Biochemical diagnosis of hypopituitarism consists of measuring the various pituitary and target hormone levels as well as provocation testing. When interpreting these tests, whether to identify excess or deficient states, it is important to remember the individual values are part of the broader hypothalamic-pituitary axis feedback loops. Thus, it can be more useful designating if a high or low test value is appropriately or inappropriately high or low. In the presented case, low TSH level could be misinterpreted as excess thyroid hormone supplementation. An appropriately elevated free T4 level would confirm this, but an inappropriately low free T4 would raise suspicion of central hypothalamic-pituitary dysfunction.
With high enough clinical suspicion of hypopituitarism, empiric treatment with thyroid supplementation and corticosteroids should be started before confirmation of the diagnosis, to prevent secondary organ dysfunction and improve morbidity and mortality.2 Rapid administration with intravenous levothyroxine can be given in severe hypothyroidism or myxedema.
“Stress-dose” steroids are generally recommended for patients who are also administered levothyroxine, as the desired increased in metabolic rate can deplete existing pituitary-adrenocortical hormone reserves, precipitating adrenal crisis.5 Stress-dose corticosteroids also ensure recruitment of a mineralocorticoid response. Cortisol has both GC and MC stimulating effects but is rapidly metabolized to cortisone, which lacks MC stimulating effects. Thus, high doses overwhelm this conversion step and allow remaining cortisol to stimulate MC receptors.2 These high doses may not be necessary in secondary AI (i.e., preserved MC function) but would be reasonable in an unstable patient or until confirmation is made with an inappropriately low ACTH.
Back to the Case
Morning cortisol returned undetectable, and ACTH was 14 pg/mL (6-58). Past records revealed a down-trending TSH from 1.12 to 0.38 mIU/mL, which had inappropriately prompted a levothyroxine dose reduction from 50 mcg to 25 mcg. A free thyroxine (T4) was low at 0.67 ng/dL (0.89-1.76). Estradiol, FSH, and LH were undetectable. Prolactin was 23 ng/mL (3-27). She was started on prednisone, 5 mg daily, and her levothyroxine was adjusted to a weight-based dose. Her fever resolved with the initiation of prednisone, and all cultures remained negative. Over two weeks, she improved back to her baseline, was discharged to a rehabilitation center, and eventually returned home.