The essence in brief:
Pituitary insufficiency is a condition characterized by the inadequate production or secretion of hormones by the pituitary gland. It can be caused by various factors such as tumors, surgery, autoimmune processes, empty sella syndrome, inflammation, or Sheehan’s syndrome.
The symptoms and clinical presentation of pituitary insufficiency depend on the specific hormones that are deficient. Common hormone deficiencies include LH/FSH (affecting menstrual cycles and fertility), ACTH (leading to cortisol deficiency), TSH (resulting in hypothyroidism), growth hormone (causing growth disturbances and metabolic issues), and prolactin (which may or may not require replacement).
Diagnosis of pituitary insufficiency involves a thorough patient history, basal hormone testing, and sometimes functional tests to confirm hormone deficiencies. Imaging techniques like magnetic resonance imaging (MRI) can help identify pituitary tumors and their effects on surrounding structures.
Treatment for pituitary insufficiency typically involves hormone replacement therapy, tailored to the specific hormones that are deficient. Medications, such as dopamine agonists for prolactinomas or growth hormone injections for growth hormone deficiency, are commonly used. Surgical intervention may be necessary for certain tumors or in cases of visual field defects.
Regular monitoring and follow-up are crucial to ensure proper hormone replacement and management of pituitary insufficiency.
Causes:
Anterior pituitary insufficiency can have the following possible causes:
Partial anterior pituitary insufficiency:
The clinical symptoms depend on the deficiency of specific pituitary hormones.
In premenopausal women, LH and FSH are responsible for the menstrual cycle. LH stimulates estrogen secretion, and FSH promotes egg maturation in the ovaries. Deficiency of these hormones leads to menstrual cycle disturbances in women and complete deficiency results in secondary ovarian insufficiency. It is called secondary because the ovaries themselves are intact but are not stimulated to function due to the lack of hormones. In postmenopausal women, LH and FSH levels are usually high due to primary ovarian insufficiency. If low LH and FSH levels are found in a postmenopausal woman, it indicates anterior pituitary insufficiency without clinical consequences. However, further investigation of the pituitary gland should still be done as other pituitary hormones may also be affected. In men, deficiency of LH and FSH leads to impotence and loss of libido. Early estrogen and testosterone deficiency can result in increased bone resorption leading to osteoporosis, decreased muscle mass and drive, and loss of body hair.
Growth hormone (GH) is essential for normal growth in children and adolescents. Deficiency of GH leads to stunted growth. GH also plays a role in hormonal function during adulthood. Loss of GH can cause metabolic disorders, muscle mass depletion, increased body fat, and impact libido, sexual function, and drive.
Prolactin is important for breast gland development during pregnancy and milk production during breastfeeding. Outside of pregnancy and lactation, deficiency of prolactin does not cause clinical changes but may indicate additional pituitary deficiencies.
Adrenocorticotropic hormone (ACTH) stimulates the adrenal glands to produce cortisol. In situations of stress and exertion, cortisol secretion is necessary for the body to cope with the demands. Deficiency of ACTH leads to weakness, fatigue, weight loss, nausea, and hypoglycemia. Increased production of melanin can result in darkening of the skin and oral mucosa, which develops gradually over months due to reduced cortisol production. Complete deficiency of ACTH can lead to an adrenal crisis in stressful situations. Cortisol is essential for survival during times of stress, and an adrenal crisis can cause loss of consciousness and requires intensive medical treatment.
Deficiency of thyroid-stimulating hormone (TSH) leads to hypothyroidism, as the thyroid gland is no longer stimulated to produce thyroid hormones. Typical clinical signs of hypothyroidism include weight gain, fatigue, constipation, circulatory problems, and various psychological changes.
Anterior pituitary insufficiency can occur acutely or slowly progress with the loss of individual pituitary hormones until complete deficiency occurs. It often begins with the deficiency of LH and FSH, followed by the gradual involvement of other hormones
Targeted patient history provides initial clues about which hormones are deficient. This is supplemented by basal hormone testing, which is often sufficient for diagnosis.
The following hormone alterations are observed in anterior pituitary insufficiency:
LH and FSH are low, and estradiol and testosterone are also low.
In cases of stunted growth, GH is low, but a low GH level is not conclusive as it can also be zero in healthy individuals. GH stimulates insulin-like growth factor 1 (IGF-1) production in the liver. Low IGF-1 levels are observed in growth hormone deficiency.
If a patient is unable to breastfeed due to pituitary insufficiency, prolactin levels are low. However, there are many other reasons why milk production may be affected.
A low ACTH and low cortisol level are not conclusive evidence of anterior pituitary insufficiency. Even in healthy individuals, ACTH and cortisol levels can be very low or undetectable. Therefore, if there is suspicion of anterior pituitary insufficiency, a functional test is necessary. The gold standard is the insulin-induced hypoglycemia test. Often, anterior pituitary insufficiency can also be demonstrated with the CRH test.
Insulin-induced hypoglycemia test:
Perform the test in the morning while the patient is fasting.
Have at least 5 vials of 40% glucose solution prepared.
1.) Insert a green venous cannula. The patient should lie down and rest until the injection.
2.) Collect serum samples for HGH, cortisol, and ACTH (= minute -15).
3.) Dilute regular insulin (e.g., Actrapid) with a small amount of NaCl to a volume of 1.0 ml and administer it intravenously: 0.15 IU, in exceptional cases 0.1 IU (Addison’s disease) or 0.2 IU (diabetes) of insulin per kg of body weight intravenously.
4.) If the patient experiences symptoms of hypoglycemia, measure blood glucose levels intermittently, but administer glucose only when the values are below 40 mg/dl. The test should continue regardless.
5.) Measure blood glucose levels and collect serum samples for HGH, cortisol, and ACTH before the insulin injection (at minute 0).
6.) Measure blood glucose levels at minutes 30, 45, and 60 (as above).
Please measure blood glucose levels again at minute 90. The patient should have breakfast soon after the test.
Evaluation: The test is only valid if blood glucose levels document a value < 40 mg/dl. An increase in HGH by < 3 ng/ml or reaching a maximum value of < 5 ng/ml (transition phase) or < 3 ng/ml (adults) provides reliable evidence of somatotropic insufficiency. A maximum value of 3/5-10 ng/ml indicates partial insufficiency.
ACTH should increase by at least 50%.
Cortisol should have a basal level > 7.2 µg/dl and increase by at least 50%. Another criterion is an increase in cortisol to > 18 µg/dl, which is considered normal.
Source: Ho, K. Consensus Guidelines. EJE (2007) 157:695-700.
Metopirone test:
Metopirone inhibits 11-β-hydroxylase in the adrenal cortex, leading to a significant increase in ACTH levels.Testing the adrenocorticotropic hormone (ACTH) and hypothalamic-pituitary-adrenal (HPA) axis function (e.g., in cases where the insulin-induced hypoglycemia test is contraindicated).
Test procedure:
At midnight, take 30 mg/kg of metyrapone (CIBA) via an international pharmacy, in the form of capsules of 250 mg, together with a glass of milk and a slice of bread (to prevent nausea).
The next morning at 8:00 am, blood samples are taken for ACTH and cortisol measurement.
Evaluation:
A morning ACTH level > 150 ng/L is considered normal.
If cortisol levels are > 8 µg/dL, metyrapone did not have sufficient effect, and the test results are not reliable.
The original test also includes the measurement of 11-deoxycortisol (11-DOC), which should increase to > 7 µg/dL (> 200 nmol/L). However, according to Allolio/Schulte “Praktische Endokrinologie,” 1st edition, p. 215, the measurement of ACTH is sufficient.
Reference: Steiner, H. et al. Exp. Clin. Endocrinol. 102 (1994) 33-38.
Arginine-GHRH test:
Perform the test in the morning while the patient is fasting.
Prescription (up to 80 kg):
L-Arginine Hydrochloride 21.0% Braun 10 x 20 ml
Intrafix Air Braun infusion set 1 piece
1.) Insert a venous cannula and flush with NaCl. The patient should lie down and rest until the infusion.
2.) Prepare the infusion solution:
Calculate the volume of the arginine concentrate: Patient’s body weight in kg x 2.5
Mix 1:1 with Aqua inject. Use a spike and a 20 ml syringe to draw an equal amount of Aqua from the glass bottle and discard it. Then add the calculated amount of arginine solution to the remaining Aqua (Ampuwa 250 ml).
If the body weight is > 45 kg, divide the arginine solution into two Aqua bottles of 250 ml each.
3.) Collect serum for HGH measurement (= Minute 0).
4.) Start the infusion immediately and let it drip rapidly (should be completed in approximately 20-30 minutes). Depending on the protocol, inject 1 ampoule of GHRH into the vein before the infusion, if instructed.
5.) After the infusion (at minute 30), collect serum for HGH measurement.
6.) Collect additional serum samples for HGH measurement at minutes 45, 60, and 90.
End of the test. Measure blood glucose levels now, as arginine can stimulate insulin release and lead to low blood glucose values. The patient should have breakfast soon after the test.
Schedule:
Insert intravenous access, Prepare the infusion solution, Collect blood samples at the following time points: Minute: 0 → Infus.→ 30, 45, 60, 90
Evaluation:
An increase in HGH levels above 10 µg/ml rules out classic growth hormone deficiency. In children, an increase to at least 19.4 µg/ml must be achieved.
Note: The test is often not evaluable in obese adolescents due to BMI dependency.
Adult reference values: > 11.5 µg/L (BMI < 25), > 8.0 µg/L (BMI 25-30), and > 4.2 µg/L (BMI > 30)
Reference: ECE 2008 Berlin, Corneli et al., Ho, K. Consensus Guidelines. EJE (2007) 157:695-700.
The medical history and laboratory investigations already indicate the diagnosis of pituitary insufficiency. In order to further investigate the underlying causes, imaging studies need to be conducted subsequently.
Imaging Techniques
Tumors in the hypothalamus or pituitary region are the most common cause of anterior pituitary insufficiency. Magnetic resonance imaging (MRI) can detect processes in the hypothalamus or pituitary region as small as 2 mm in size.
Tumors of the pituitary gland can compress the optic chiasm (optic nerve crossing). This leads to visual field defects in the upper outer quadrants. An ophthalmological examination with visual field measurement provides information on the presence of any visual field impairment.
Prolactinomas are common pituitary tumors that respond very well to dopamine agonists, and therefore, medical treatment is almost always performed.
Tumors causing acromegaly or Cushing’s disease require surgical intervention. Prior to surgery, hormonal diagnostics must always be performed. Hormonally inactive adenomas can also lead to the deficiency of specific pituitary hormones and therefore need to be operated on. Hormonally inactive adenomas can grow to a size that causes visual field defects and brain pressure problems, necessitating surgery. After surgery, partial or complete anterior pituitary insufficiency may occur.
The medical treatment of anterior pituitary insufficiency involves substituting the deficient hormones.
The deficiency of ACTH leads to cortisol deficiency. The medical treatment is carried out using hydrocortisone and occasionally long-acting corticosteroids. The treatment is described in the section on Cushing’s disease and Cushing’s syndrome.
In the case of TSH deficiency, thyroid hormone replacement is necessary. This is achieved with levothyroxine or a combination of levothyroxine and triiodothyronine. Detailed information about the treatment can be found in the section on the thyroid.In cases of hypopituitarism with TSH deficiency, adrenal insufficiency must be ruled out before initiating levothyroxine therapy. Levothyroxine increases metabolic activity and, consequently, the body’s need for cortisol. If an untreated cortisol deficiency is present, this may trigger an Addisonian crisis. In children in particular, this can lead to life-threatening complications and even death.
Prolactin does not need to be replaced.
Growth hormone deficiency in children and adolescents is treated with daily subcutaneous injections of growth hormones into the fatty tissue. The dosage of growth hormone is adjusted to maintain IGF-1 levels within the normal range, thus enabling normal growth.
Growth hormone deficiency in adults can also lead to significant impairments, as described above. Treatment with growth hormone is also performed in adults, and the dosage of growth hormone is guided by IGF-1 levels. However, the presence of growth hormone deficiency in adults must be clearly demonstrated through the corresponding functional tests. The gold standard for diagnosis is the insulin-induced hypoglycemia test.
In women with LH and FSH deficiency, substitution with estradiol is carried out in premenopausal women. In cases of fertility desire, treatment with LH/FSH analogs to induce ovulation is also possible. This treatment is performed in fertility centers with relevant expertise, as multiple pregnancies can occur as a result of treatment.
In men, the absence of LH and FSH leads to testosterone deficiency (hypogonadotropic hypogonadism). Hormone replacement therapy is performed with intramuscular testosterone injections or testosterone-containing gels, which need to be applied daily to the upper arms, abdomen, or inner thigh depending on the specific product. In cases of fertility desire, treatment with LH/FSH analogs can also be attempted.
A detailed description of hormone replacement therapy in patients with LH/FSH deficiency can be found in the section on Testes (Male Gonads)