Panhypopituitarism

Physiology^1,2,3

• Pituitary hormone secretion is tightly controlled by the hypothalamus. The hypothalamus regulates the anterior pituitary via hormonal signals (hypothalamic releasing and inhibitory hormones), and the posterior pituitary via neuronal signals (Figure 1).

Anterior Pituitary (Adenohypophysis)

The anterior pituitary secretes the following hormones.

• Growth Hormone (GH): GH controls body growth by stimulating cell replication, differentiation, and protein synthesis. It stimulates the release of insulin-like growth factor 1 and lipolysis. It also counteracts insulin’s effects on carbohydrate and lipid metabolism.
• Adrenocorticotropic hormone (corticotropin, ACTH): ACTH controls the production and release of corticosteroids and androgens by the adrenal cortex.
• Thyroid-stimulating hormone (thyrotropin, TSH): TSH controls the production and release of thyroxine and triiodothyronine by the thyroid gland, which regulate the rate of body metabolism.
• Prolactin: Prolactin controls mammary gland growth and milk production.
• Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH): FSH controls the growth of ovarian follicles and spermatogenesis in the testis. LH controls the production and release of estrogen and progesterone by the ovaries and testosterone by the testes. LH also promotes ovulation and the formation of the corpus luteum in the ovaries.

Posterior Pituitary (Neurohypophysis)

The posterior pituitary secretes the following hormones.

• Antidiuretic hormone (ADH, Vasopressin): ADH controls the water reabsorption rate via the collecting ducts and tubules of the kidneys and regulates body water content
• Oxytocin: Oxytocin controls infant delivery at the end of gestation by causing powerful contractions of the uterus. It also causes milk to be released from the alveoli into the ducts for milk expression.
• Posterior pituitary hormones are synthesized by the hypothalamus (supraoptic and paraventricular nuclei) and transported to the posterior pituitary gland to be released.

Pathophysiology⁴

Panhypopituitarism refers to decreased production/secretion of hormones from the pituitary. It can be caused by both hypothalamic and pituitary disorders.

Hypothalamic Disorders: can affect both anterior and posterior pituitary hormones.

• Tumors: These include benign tumors such as craniopharyngiomas or malignant metastasis (breast and lung carcinomas).
• Radiation Therapy: When brain or nasopharyngeal tumors are treated with radiation in children or adults, hypothalamic hormone deficiency can occur, which results in downstream pituitary hormone deficiencies. This effect is both dose and time-dependent.
• Infiltrative Lesions: Infiltrative conditions such as sarcoidosis and Langerhans cell histiocytosis can invade the sella region and cause hormone deficiencies.
• Infections: Hypopituitarism can follow CNS infection, such as meningitis, which can be caused by a variety of agents (e.g., tuberculosis, streptococcus). It is more likely in immunocompromised patients.
• Traumatic brain injury: Severe trauma to the brain can cause hypothalamic hormone deficiencies, especially those involving fractures to the skull base. The likelihood is directly related to the severity of the initial injury. Incidents of hypopituitarism can occur even in the absence of direct injury to the hypothalamus or pituitary.
• Stroke: Both ischemic and hemorrhagic strokes can be associated with pituitary dysfunction.

Pituitary Disorders

• Macroadenomas: Primary pituitary tumors, such as pituitary macroadenomas (greater than 10 mm), are often associated with hypopituitarism.
• Mass Lesions: Mass lesions such as cysts, metastatic cancer, and lymphocytic infiltrates can cause hypopituitarism. Decompression of the mass may restore function.
• Transsphenoidal Surgery: When attempting to resect a pituitary adenoma, normal pituitary tissue can be inadvertently excised. If enough normal cells are resected, hypopituitarism can occur.
• Pituitary Radiation: When radiation is used to curb the regrowth of residual adenomatous tissue after surgery, normal pituitary tissue is subjected to the same radiation, and hypopituitarism can result.
• Hereditary Hemochromatosis: Iron deposits in pituitary cells can cause hypopituitarism, with GH deficiency being the most common. Repeated phlebotomy to treat the condition may restore GH production.
• Hypophysitis: Inflammation of the pituitary can cause hypopituitarism. There are several causes: lymphocytic (most common), granulomatous, plasmacytic (IgG4- associated), and xanthomatous. It can also occur as a complication of immunotherapy with immune checkpoint inhibitors (e.g., ipilimumab).
• Pituitary Infarction: Infarction of the pituitary in the setting of postpartum hemorrhage is a well-known entity called Sheehan Syndrome. It is usually associated with hypotension and transfusion requirements. Symptoms of hypopituitarism can present in days or weeks after delivery with eventual development of an empty sella.
• Pituitary Apoplexy: Hemorrhage into the pituitary gland, typically from an adenoma, can also cause hypopituitarism. Patients typically present with additional symptoms, including headaches and diplopia.
• Infection/Abscess: Pituitary gland infections are rare and can be caused by several organisms, including TB, candida, and hantavirus.
• Genetic Diseases: Congenital deficiencies of pituitary hormones can be caused by mutations in genes encoding transcription factors. As a result of these mutations, the anterior pituitary cells fail to differentiate appropriately.
• Pituitary Stalk Interruption Syndrome (PSIS): Congenital hypopituitarism can be associated with a combination of imaging abnormalities called PSIS: small pituitary, thinned or interrupted stalk, and ectopic neurohypophysis
• Empty Sella: Empty sella syndrome refers to the findings of an empty sella on MRI: enlarged sella turcica and relative paucity of pituitary tissue.
  • Primary: A defect in the diaphragm sella allows cerebrospinal fluid (CSF) to enter the sella and enlarge it.
  • Secondary: This is associated with a known prior insult to the pituitary gland, like infection or mass effect from an adenoma.

Symptoms and Treatment^5-8

Anterior Pituitary Hormone Deficiencies

GH

• Children: Generalized deficiencies of pituitary hormones will result in dwarfism. The different parts of the body develop in proportion to each other, but the overall growth rate is greatly reduced. They may also never go through puberty due to a lack of gonadotropins.
• Adults: GH deficiency results in decreased lean body mass, bone mineral density, and quality of life. Patients develop increased fat mass, dyslipidemia, and cardiovascular disease. They have an increased incidence of fractures and a decreased life expectancy.
• Treatment: Replace GH with recombinant human GH, titrate to insulin-like growth factor-1 (IGF-1) levels. There is strong evidence that GH replacement increases muscle mass and decreases fat mass. The evidence for improvement in bone density or cardiovascular disease is limited.

Adenocorticotropic Hormone (Corticotropin, ACTH)

• Symptoms: Symptoms of ACTH deficiency result primarily from cortisol insufficiency. In severe form, it can lead to vascular collapse due to the inability to maintain peripheral vascular tone. Less severe cases can have a variety of clinical findings, including postural hypotension, tachycardia, fatigue, weight loss, etc.
• Primary vs. Secondary Adrenal Insufficiency: There are important differences between ACTH deficiency (secondary) and primary adrenal insufficiency (Addison’s Disease). In ACTH deficiency, there is no aldosterone deficiency and no issues with salt wasting/hyperkalemia. There is also no hyperpigmentation associated.
• Treatment: Administer hydrocortisone, as this is the same compound as cortisol, normally made by the adrenal glands. Doses are usually 15-25 mg, given as a single or divided dose, as this is similar to daily production rates. However, there is no objective test to assess the adequacy of replacement.

Thyrotropin, TSH

• Symptoms: Common signs of thyroid hormone deficiency include fatigue, cold intolerance, decreased appetite, constipation, dry skin, delayed relaxation of deep tendon reflexes, facial puffiness, and anemia. Cardiac symptoms include bradycardia, decreased cardiac output, and increased peripheral vascular resistance.
• Treatment: Before starting thyroid hormone replacement therapy, it is important to ensure that patients have adequate cortisol replacement. Levothyroxine (T4) can increase renal clearance of cortisol, worsening cortisol deficiency. Replace with weight-based T4 dose of 1.6 mcg/kg to maintain serum free T4 slightly higher than mid-normal, since TSH cannot be used to assess adequacy of thyroid replacement.

Prolactin

• Symptoms: The only known clinical symptom of prolactin deficiency is the inability to lactate after childbirth.
• Treatment: none available.

FSH and LH

Deficiencies in FSH and LH result in hypogonadotropic hypogonadism (secondary hypogonadism) in both males and females, but the clinical symptoms differ.

Women:

• Premenopausal: Before menopause, ovarian hypofunction results in anovulation and decreased estradiol secretion. Symptoms include irregular periods/amenorrhea, infertility, hot flashes, and vaginal atrophy. Long-term complications can include decreased bone mineral density and decreased breast tissue mass.
• Treatment: Patients should be on estradiol replacement that mimics natural secretion by the ovaries. Patients with an intact uterus should also take a progestin to avoid the risk of endometrial hyperplasia/carcinoma.
• Postmenopausal: After menopause, there are usually no clinical symptoms despite a lower-than-normal serum level of FSH and LH.
• Treatment: None necessary

Men:

• Symptoms: Testicular hypofunction leads to decreased spermatogenesis and reduced testosterone secretion. Testosterone deficiency causes decreased energy and libido as well as hot flashes, and can cause long-term decreases in muscle mass.
• Treatment: Testosterone replacement is indicated similarly to primary hypogonadism, while treatment adequacy is assessed via serum testosterone levels. If fertility is desired, then patients should be treated with gonadotropins to induce spermatogenesis.

Posterior Pituitary Hormone Deficiencies

ADH, Vasopressin

• Symptoms: ADH deficiency is also called central diabetes insipidus. Initial presenting symptoms include polydipsia and large volume, dilute urine output. Serum sodium concentration is usually in the high-normal range but can be severe in patients without access to free water.
• Treatment: Replace with desmopressin in a variety of formulations (intranasal, oral, or parenteral) with the primary goal of reducing urine output. Serum sodium should be monitored for the risk of hyponatremia.

Oxytocin

• Symptoms: oxytocin deficiency has no overt clinical signs unless peripartum.
• Treatment: Can be replaced with oxytocin in the peripartum setting.

Perioperative Management^2,9

Perioperative considerations primarily involve three pituitary hormones: thyrotropin, corticotropin, and ADH.

Thyroid

• Thyroid function should be assessed preoperatively within 3-6 months. In patients with hypopituitarism, free T4 levels should be obtained rather than TSH levels.
• Complications of hypothyroidism: Perioperative risks in patients with hypothyroidism vary by degree of thyroid dysfunction. In severe cases, patients can develop myxedema coma as well as cardiac and respiratory compromise.
• Cardiac dysfunction can include reduced cardiac output (30-50%), intraoperative hypotension, coronary ischemia, and cardiac arrhythmias.
• Respiratory issues can include impaired hypoxic and hypercapnic respiratory drive, respiratory muscle weakness, and increased prevalence of obstructive sleep apnea (OSA).
• Hypothyroid patients can also have additional anesthetic concerns, including difficult airway (laryngeal myxedema/macroglossia) and increased sensitivity to anesthetic agents. Myxedema coma, consisting of altered mental status, hypotension, bradycardia, hypothermia, and metabolic abnormalities, is a complication of severe hypothyroidism that has a high mortality rate.

Corticotropin

• Stress dose steroids are necessary for patients on long-term maintenance hydrocortisone. Please see the OA summary: Adrenal Insufficiency and Perioperative Corticosteroids. Link

Central DI

• ADH deficiency can be treated perioperatively with DDAVP combined with an isotonic crystalloid solution.
• Serum sodium and osmolality should be measured regularly. Intranasal DDAVP can also be used and has prolonged antidiuretic activity (12-24 hours).
• Other options include a thiazide diuretic or vasopressin infusion.