Hypopituitarism

Medical Experts

Contributor

Doyle

Kelly Doyle, PhD, DABCC, FAACC

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry and Endocrinology, ARUP Laboratories

Contributor

Straseski

Joely A. Straseski, PhD, MS, MT(ASCP), DABCC, FAACC

Professor of Pathology (Clinical), University of Utah

Head of Clinical Operations for Clinical Chemistry, Toxicology, and Biochemical Genetics; Medical Director, Endocrinology; Co-Director, Automated Core Laboratory, ARUP Laboratories

Hypopituitarism is the partial or total deficiency of at least one of the hormones produced by the pituitary gland. Panhypopituitarism occurs when the production of all pituitary hormones has decreased, and patients may transition from hypopituitarism to panhypopituitarism over time. The anterior lobe of the pituitary gland produces adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone, prolactin, and gonadotropins (i.e., luteinizing hormone [LH] and follicle-stimulating hormone [FSH]). The posterior lobe produces oxytocin and arginine vasopressin (AVP). A decrease in the production of various pituitary hormones often, though not always, occurs in the following order: growth hormone and gonadotropins, TSH, then ACTH and prolactin. Laboratory testing for the diagnosis of hypopituitarism may include an assessment of hormones produced by the pituitary gland as well as hormones produced by the glands stimulated by the pituitary gland (e.g., thyroxine and cortisol, which are produced by the thyroid and adrenal glands, respectively).

Quick Answers for Clinicians

What are the common causes of hypopituitarism?

Hypopituitarism and panhypopituitarism are most commonly caused by benign pituitary tumors or the treatment of such tumors by pituitary surgery radiotherapy. Other causes include traumatic brain injuries (TBIs), pituitary apoplexy, hemochromatosis, and certain infectious diseases. In children, hypopituitarism may be congenital and may be caused by structural abnormalities of the pituitary gland or by certain craniofacial defects.

Which hormonal interactions need to be considered when assessing pituitary hormones?

The various hormones produced or regulated by the pituitary gland, including hormones of the hypothalamic-pituitary-adrenal (HPA) axis, affect one another to various degrees. These interactions have clinical implications and entail additional testing considerations in individuals with adrenal insufficiency, central hypothyroidism, growth hormone deficiency, hypogonadism, and diabetes insipidus.^,

Because of the complex interactions among these hormones, the following should be considered when evaluating specific conditions associated with hypopituitarism:

Condition	Laboratory Testing Considerations
Central adrenal insufficiency	Assess HPA axis functionality before and after growth hormone replacement therapy Monitor for diabetes insipidus in individuals being treated for adrenal insufficiency If diabetes insipidus improves in patients without an adrenal insufficiency diagnosis, perform adrenal insufficiency testing Estrogen replacement therapy can elevate serum cortisol levels, which may affect adrenal evaluation
Central hypothyroidism	Monitor thyroid function in patients receiving therapy for growth hormone deficiency Treat central hypothyroidism before assessing for growth hormone deficiency
Growth hormone deficiency	Assess HPA axis functionality before and after starting growth hormone replacement therapy Monitor thyroid function in patients receiving therapy for growth hormone deficiency Treat central hypothyroidism before assessing for growth hormone deficiency
Hypogonadotropic hypogonadism	Estrogen replacement therapy can elevate serum cortisol levels, which may affect adrenal evaluation
Diabetes insipidus	Monitor for diabetes insipidus in individuals being treated for adrenal insufficiency If diabetes insipidus improves in patients without an adrenal deficiency diagnosis, test for adrenal insufficiency
Sources: Fleseriu, 2016; Feldt-Rasmussen, 2018

Indications for Testing

Testing for hypopituitarism should be performed if clinical suspicion for a pituitary hormone deficiency exists, if deficiency of at least one pituitary hormone has been documented, or if a condition that is known to cause hypopituitarism is present (e.g., pituitary incidentaloma, traumatic brain injury, treatment of pituitary adenomas through surgery or radiotherapy).^,^, Symptoms may help guide initial testing.

Hormone Deficiencies Caused by Hypopituitarism
Deficient Hormone(s)	Associated Disorder	Common Symptoms	Other ARUP Consult Resources
ACTH	Central adrenal insufficiency	Chronic: lethargy, weight loss, tiredness Acute: nausea, hypotension, hyponatremia, vomiting	Adrenal Insufficiency topic Adrenal Insufficiency Testing Algorithm
Growth hormone	Growth hormone deficiency	Children: reduced growth Adults: low energy, increased fat mass, decreased muscle mass	Growth Hormone Deficiency topic Growth Hormone Testing in Pediatric Patients Testing Algorithm Growth Hormone Testing in Transition Patients Testing Algorithm Growth Hormone Testing in Adult Patients Testing Algorithm
TSH	Central hypothyroidism	Fatigue, cold intolerance, weight gain (with reduced severity compared to primary hypothyroidism)	Hypothyroidism topic Thyroid Disease Testing Algorithm
LH and FSH (gonadotropins)	Hypogonadism (male and female)	Premenopausal individuals with ovaries: amenorrhea or irregular menstruation, fertility issues Individuals with testes: testosterone deficiency, infertility	Male Hypogonadism topic Hypogonadism Testing Algorithm Amenorrhea topic Amenorrhea Testing Algorithm
Prolactin	Hyperprolactinemia (leading to hypogonadism)	Premenopausal individuals with ovaries: amenorrhea or irregular menstruation, fertility issues Individuals with testes: testosterone deficiency, infertility	Male Hypogonadism topic Hypogonadism Testing Algorithm Amenorrhea topic Amenorrhea Testing Algorithm
Prolactin	Hypoprolactinemia	Inadequate lactation	—
AVP	Central diabetes insipidus	Excessive urine production, excessive thirst	Central Diabetes Insipidus (Posterior Pituitary) Testing Algorithm
Sources: Fleseriu, 2016; Higham, 2016

Pituitary Hormone Testing

If hypopituitarism is suspected, evaluations should be performed for all hormones released by the pituitary gland. Because some analytes (particularly estradiol, testosterone, growth hormone, and free thyroxine) have large interassay variability, the same assay from the same laboratory should be used for all serial measurements.

Adrenocorticotropic Hormone

Because ACTH regulates the production of cortisol, decreased ACTH production may result in adrenal insufficiency. High ACTH concentrations are associated with primary adrenal insufficiency. For detailed information on the diagnosis of primary adrenal insufficiency, refer to the ARUP Consult Adrenal Insufficiency topic.

Because low to normal levels of ACTH do not necessarily indicate central adrenal insufficiency, the initial test for the assessment of central adrenal insufficiency is serum cortisol, measured in the morning. Low cortisol concentrations indicate adrenal insufficiency, whereas high cortisol concentrations likely rule it out.

When initial serum cortisol concentrations are indeterminate, a corticotropin stimulation test should be performed, and cortisol should be measured 30 or 60 minutes after the administration of cosyntropin. A high result suggests a diagnosis of central adrenal insufficiency, whereas a low result suggests primary adrenal insufficiency. Either a high-dose or low-dose test may be used. This test has a low specificity, which should be considered along with the pretest probability of the disease when approaching diagnosis.

For individuals taking hydrocortisone or glucocorticoids, any testing of the hypothalamus-pituitary-adrenal (HPA) axis should be performed at least 18-24 hours after the last dose of hydrocortisone and longer after the last dose of synthetic glucocorticoids.

Growth Hormone

When a strong clinical suspicion of growth hormone deficiency (GHD) exists in conjunction with deficits in at least three other pituitary hormones, biochemical testing for GHD is not recommended. For detailed information on the diagnosis of GHD, refer to the ARUP Consult Growth Hormone Deficiency topic.

After the initiation of GH replacement therapy, thyroid function and adrenal function should be assessed.

Thyroid-Stimulating Hormone

Central hypothyroidism usually occurs in the presence of other pituitary hormone deficiencies. For detailed information on the diagnosis of hypothyroidism, refer to the ARUP Consult Hypothyroidism topic.

Luteinizing Hormone and Follicle-Stimulating Hormone

Deficiencies in the pituitary gonadotropins (LH and FSH) result in central hypogonadotropic hypogonadism in both individuals with testes and individuals with ovaries.

Individuals With Testes

In individuals with testes, hypogonadotropic hypogonadism may result in low testosterone and/or impaired spermatogenesis. For detailed information about the diagnosis of hypogonadism in individuals with testes, refer to the ARUP Consult Male Hypogonadism topic.

Individuals With Ovaries

In individuals with ovaries, hypogonadotropic hypogonadism may result in amenorrhea or oligomenorrhea. In individuals with these symptoms, other causes of impaired ovulation (e.g., thyroid disease and hyperandrogenism) should be ruled out, especially in individuals without deficiencies in other pituitary hormones. Refer to the ARUP Consult Amenorrhea topic for the appropriate workup.

Serum estradiol, FSH, and LH should be measured when assessing for hypogonadotropic hypogonadism in individuals with ovaries. In premenopausal individuals, low serum estradiol combined with low LH and low FSH concentrations suggests a diagnosis of hypogonadotropic hypogonadism, although the results must take the menstrual cycle phase into account. In postmenopausal individuals, an absence of elevated FSH and LH confirms a diagnosis of hypogonadism, as long as the patient is not receiving hormone replacement therapy.

Dynamic testing for gonadotropin-releasing hormone (GnRH) does not provide useful diagnostic information.

Prolactin

Hypopituitarism may be associated with either hypoprolactinemia or hyperprolactinemia (which can cause hypogonadism).^, A single elevated serum prolactin measurement establishes the diagnosis of hyperprolactinemia unless there is high venipuncture stress. For more information on the appropriate follow-up to a diagnosis of hyperprolactinemia, refer to the Endocrine Society's clinical practice guidelines.

Arginine Vasopressin

A deficiency in AVP, also referred to as antidiuretic hormone (ADH) or arginine vasopressin hormone (AVH), can result in diabetes insipidus.^, Testing is used to differentiate between primary polydipsia (in which excessive thirst and fluid consumption lead to dilute urine), central diabetes insipidus (caused by low AVP secretion due to damage of the hypothalamus or pituitary gland), and nephrogenic diabetes insipidus (caused by impaired kidney function that results in the ability to concentrate urine).^,

Given the technical difficulties in directly quantifying plasma AVH, plasma copeptin serves as a reliable surrogate marker.^,

Copeptin

Copeptin is a component of the precursor to AVP. It is cosecreted with AVP from the posterior lobe in response to physiologic stimuli and is present in plasma at concentrations similar to those of AVP.^, Due to the strong correlation of plasma copeptin with AVP, its greater ex vivo stability, and ease of testing, copeptin is utilized with high diagnostic accuracy as a surrogate marker for AVP in testing for diabetes insipidus.^, Refer to the ARUP Consult Central Diabetes Insipidus (Posterior Pituitary) Testing Algorithm for more information.

Initial Testing

Initial testing for diabetes insipidus should include measurements for urine osmolality, serum osmolality, and sodium levels.^,

Interpretation of Urine and Serum Osmolality Test Results
Urine Osmolality	Serum Osmolality	Interpretation
Low	Low	Suggests primary polydipsia
Low	High	Suggests diabetes insipidus
Source: Gubbi, 2019

Water Deprivation Test

If results are inconclusive or suggest diabetes insipidus, a water deprivation test, long considered the standard diagnostic test for diabetes insipidus, should be performed. Urine osmolarity, serum osmolarity, and sodium levels are measured after a period of dehydration; the results of this test can often definitively differentiate between diabetes insipidus and primary polydipsia.

Central diabetes insipidus and nephrogenic diabetes insipidus can be differentiated by measuring urine osmolarity after administration of desmopressin.

Recent studies suggest plasma copeptin coupled with hypertonic saline infusion have a higher diagnostic accuracy than water deprivation tests and may be used as an alternative, if available. Refer to the ARUP Consult Central Diabetes Insipidus (Posterior Pituitary) Testing Algorithm for more information.