CLINICAL RECOGNITION

Hypopituitarism usually has an insidious presentation over weeks to months and often remains clinically silent until a particular stressful event such as a concurrent infection or trauma at which time marked symptoms are evident. The reason for a protracted course until deficiency is clinically evident is due to the slow depletion of pituitary hormones. The end endocrine organs also have other, albeit less effective, ways of dealing with lack of pituitary input (for example non ACTH stimulation of cortisol from the adrenal or constitutive activation of the TSH receptor at a low level in the thyroid). The presentation of hypopituitarism is different from the catastrophic clinical situation such as a hemorrhagic infarct into the pituitary that results in acute pituitary insufficiency and cardiovascular collapse. The latter is referred to as pituitary apoplexy and is discussed in another chapter. The more common presentation is in a patient who slowly develops fatigue and rather nonspecific symptoms.

Each cell in the pituitary is responsible for one or more pituitary hormones and hyposecretion of the hormone can result in a variety of symptoms as summarized in Table 1. Although the symptoms are rarely pathognomonic for hypopituitarism or a particular hormone insufficiency, collectively the presence of symptoms such as body fatigue and failure to thrive with or without cardiovascular compromise in the right clinical scenario, should alert the physician to a pituitary etiology.

Table 1. Signs of Symptoms of Hypopituitarism in Adults

Often times, patients with panhypopituitarism can present with slight elevation, as opposed to deficiency, in prolactin levels causing amenorrhea and/or galactorrhea. This is because damage to the pituitary stalk (usually from mass effect) can cause interruption of the continuous dopaminergic inhibition of the lactotrophs resulting in elevated prolactin levels (usually less than 200 ng/mL). It is important to be able to differentiate this entity from a prolactinoma, which usually presents with levels above 200ng/mL.

Hypopituitarism can also manifest with deficiency of antidiuretic hormone if there is damage to the posterior pituitary. This will cause the clinical syndrome known as diabetes insipidus, which classically manifests with polyuria, polydipsia, hypernatremia and low urine osmolarity.

Often it will be difficult for the physician at the bedside to determine whether the suspected hormone deficiency is in fact due to a pituitary insufficiency or primary failure of one of the major endocrine glands such as the adrenal, thyroid or gonads. While some clues may come from the history, the suggestion that one or more endocrine glands are dysfunctional should alert the physician to a pituitary etiology. The presenting signs and symptoms are similar in both children and adults although the presentation in children is usually much more dramatic. The signs are more often associated with cardiovascular instability, failure to gain weight or grow depending on the degree of pituitary hormone deficiency and can be present at birth or later.

PATHOPHYSIOLOGY

The etiologies of hypopituitarism are either congenital or acquired. While congenital hypopituitarism is usually associated with early onset hemodynamic instability, growth disturbances and failure to thrive the symptoms may not manifest until puberty when a surge in pituitary hormones is required for normal physiology, and puberty is halted. Although isolated pituitary hormone deficiencies are found (usually due to genetic defects in specific pituitary cell transcription factors), when two pituitary cell lines are impaired it is generally an indication that all five cell lines are malfunctioning. There is however, a predictive order of loss of hormonal function, with a tendency to preserve the most crucial hormones for survival. (Usually manifesting first with loss of somatotrophs and gonadotrophs and last with loss of corticotroph function). The acquired causes of hypopituitarism are listed in Table 2. One should also consider the possibility of hypothalamic disease as a cause of pituitary insufficiency.

DIAGNOSIS AND DIFFERENTIAL

TREATMENT

The objective of treatment of hypopituitarism is to replace deficient hormones. It is usually not practical to directly replace the pituitary hormone, but rather treatment is with the end-organ hormone (e.g. thyroid hormone is used for TSH deficiency rather than TSH and corticosteroids for ACTH deficiency rather than ACTH).

In general, it is recommended to begin by replacing the hormones with more critical metabolic functions first. Glucocorticoids should be instituted first to avoid an adrenal crisis, followed by thyroid replacement therapy and after this if appropriate, gonadal and growth hormone replacement.

Titration of glucocorticoid replacement is quite challenging, as one cannot rely on cortisol or ACTH levels to assess for under or over replacement. The corticosteroid replacement dose is usually estimated based on body mass weight and delivered at different doses throughout the day trying to mimic as much as possible its physiologic circadian rhythm. The recommended doses in table 4are guidelines only and need to be titrated by the bedside physician based on the specific clinical situation. It is extremely important to emphasize to other clinicians and patients with adrenal insufficiency, that during acute sickness and high stress situations, higher doses of glucocorticoid replacement are needed.

Thyroid replacement therapy is somewhat easier to titrate, as free T4 levels can be quite useful. The clinician however, should avoid the mistake of following TSH levels, as they will not be useful in secondary hypothyroidism.

FOLLOW-UP

After the diagnosis is made and acute treatment is started (Table 4, Acute) a decision needs to be made whether continued chronic therapy with hormone replacement is needed. A month after discharge from the hospital and recovery from the acute event, if necessary, patients are retested to determine if the endocrine defect persists. This will depend on the etiology, removal of tumor or reversal of an infiltrative process sometimes allows recovery of function. Repeat testing will confirm whether the patient needs to remain on life-long hormone replacement therapy.

REFERENCES

1. J. Yeo KT, Babic N, Hannoush Z, Weiss RE. Endocrine Testing Protocols: Hypothalamic Pituitary Adrenal Axis. Endotext 2017. PMID: 25905177

http://www.endotext.org/chapter/endocrine-testing-protocols-hypothalamic-pituitary-adrenal-axis/

2.

Maria Fleseriu, Ibrahim A. Hashim, Niki Karavitaki, Shlomo Melmed, M. Hassan Murad, Roberto Salvatori, Mary H. Samuels; Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 11, 1 November 2016, Pages 3888–3921, https://doi​.org/10.1210/jc.2016-2118