Hypopituitarism

Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. The hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview produced from this lobe are growth hormone, follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone, and prolactin. When the posterior lobe (neurohypophysis) is also damaged, loss of antidiuretic hormone and oxytocin occurs. All of these hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview regulate the activities of different organs, and thus the effects of pituitary hypofunction are multisystemic. The diagnosis is made through a combination of clinical findings, hormone levels, provocation tests, and brain imaging. Treatment is hormone replacement and addressing the etiology.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Hypopituitarism is the condition resulting from inadequate production of pituitary hormones Pituitary hormones The hypothalamic and pituitary hormones are the most important regulators of the endocrine system. The hypothalamus functions as the coordinating center between the CNS and endocrine system by integrating the signals received from the rest of the brain and releasing appropriate regulatory hormones to the pituitary gland. The pituitary gland then releases its own hormones in response to hypothalamic stimulation. Hypothalamic and Pituitary Hormones:

  • Primary hypopituitarism: disorders of the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland
  • Secondary hypopituitarism: disorders of the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus

Epidemiology

  • < 200,000 people affected in the United States
  • Average yearly incidence rate of 4.21 cases per 100,000
  • No difference in incidence between sexes

Etiology

  • Masses/tumors:
    • Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas/tumors (approximately 50% of cases)
    • Rathke’s cleft cyst
    • Meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma
    • Craniopharyngioma Craniopharyngioma Craniopharyngiomas are rare squamous epithelial tumors with a solid and/or cystic structure that arise from the remnants of Rathke's pouch along the pituitary stalk, in the suprasellar region. Craniopharyngiomas are histologically benign but tend to invade surrounding structures; thus, they should be treated as low-grade malignancies. Craniopharyngioma
    • Lymphocytic hypophysitis (infiltration of lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes causing pituitary enlargement)
  • Systemic causes:
    • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
    • Granulomatosis with polyangiitis Granulomatosis with Polyangiitis Granulomatosis with polyangiitis (GPA) is a rare autoimmune disease of unknown etiology. It leads to a necrotizing granulomatous inflammation of small and medium-sized blood vessels of the nose, sinuses, throat, lungs, and kidneys. Granulomatosis with Polyangiitis
    • Hemochromatosis
    • Histiocytosis X
    • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
  • Congenital causes:
    • Pituitary dysplasia: hypoplasia/aplasia/ectopic development
    • Kallman syndrome: defective hypothalamic gonadotropin-releasing hormone (GNRH)/GNRH synthesis
    • Prader–Willi syndrome: varying degrees of hypopituitarism with hyperphagia– obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, hypotonia, developmental delay, and diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Tissue-specific factor mutations
  • Traumatic causes: 
    • Brain injury
    • Surgery
    • Radiotherapy 
  • Infectious causes 
    • Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis
    • Candidiasis Candidiasis Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis
  • Vascular causes:
    • Sheehan’s syndrome: postpartum pituitary necrosis caused by blood loss during childbirth
    • Pituitary apoplexy: sudden hemorrhage of the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland, often in the presence of a pituitary adenoma
    • Carotid artery aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Extremity and Visceral Aneurysms
    • Subarachnoid hemorrhage Subarachnoid Hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most SAHs originate from a saccular aneurysm in the circle of Willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage (SAH)
  • Empty sella syndrome (radiologic finding):
    • May result from:
      • Surgically removed pituitary tumor
      • Cerebrospinal fluid flowing through a defect and filling the space
    • Hypopituitarism can arise insidiously owing to the above processes.

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Pathophysiology

Pituitary gland

  • Also called hypophysis
  • Function: stimulation and/or suppression of activity of the major endocrine glands through secretion of hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview
  • Two lobes with own set of secretory products and feedback loops: 
    • Anterior (adenohypophysis):
      • Growth hormone (GH)
      • Luteinizing hormone (LH)
      • Follicle-stimulating hormone (FSH)
      • Prolactin (PRL)
      • Thyroid-stimulating hormone (TSH)
      • Adrenocorticotropic hormone (ACTH)
    • Posterior (neurohypophysis):
      • Antidiuretic hormone (ADH) or vasopressin
      • Oxytocin
  • Decreased function, or hypopituitarism, is most noted with anterior pituitary lobe damage, as it makes up 80% of the gland.
Hypothalamic–pituitary complex

Hypothalamic–pituitary complex:
The image shows the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland, made up of the anterior and posterior lobes, in relation to the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus.

Image: “1806 The Hypothalamus-Pituitary Complex” by OpenStax College. License: CC BY 3.0

Loss of pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland function

  • Damage to the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland → sequential loss of anterior pituitary hormones Pituitary hormones The hypothalamic and pituitary hormones are the most important regulators of the endocrine system. The hypothalamus functions as the coordinating center between the CNS and endocrine system by integrating the signals received from the rest of the brain and releasing appropriate regulatory hormones to the pituitary gland. The pituitary gland then releases its own hormones in response to hypothalamic stimulation. Hypothalamic and Pituitary Hormones:
    • Because of vulnerability to pressure, GH-secreting cells (somatotrophs) are affected first → ↓ GH occurs
    • Followed by ↓ LH and FSH (gonadotropins) → ↓ TSH → ↓ ACTH
    • PRL rarely affected (if deficient, suggestive of total anterior pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland failure)
  • General effect: decreased target gland hormone production
Hormones of anterior pituitary: target organs, function, and effects
Hormone Pituitary cell type Target organ Function Decreased production
ACTH Corticotroph Adrenal cortex Stimulates:
  • Cortisol
  • Androgen
  • Aldosterone
Secondary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
GH Somatotroph Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and other tissues Stimulates protein synthesis and overall growth of most cells and tissues
  • Short stature
  • GH deficiency
Prolactin Lactotroph Mammary glands
  • Secretion of milk
  • Female breast development
Inability to produce milk (hypoprolactinemia)
TSH Thyrotroph Thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland Stimulates the thyroid gland to synthesize and secrete thyroid hormone Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
LH Gonadotroph
  • Ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries
  • Testes
  • Ovulation, estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries and progesterone synthesis
  • Testosterone production from interstitial Leydig cells
  • Hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism
  • Kallman syndrome
  • Pasaqualini’s syndrome
FSH Gonadotroph
  • Ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries
  • Testes
  • Growth of follicles in ovaries
  • Sperm maturation
  • Hypogonadism Hypogonadism Hypogonadism is a condition characterized by reduced or no sex hormone production by the testes or ovaries. Hypogonadism can result from primary (hypergonadotropic) or secondary (hypogonadotropic) failure. Symptoms include infertility, increased risk of osteoporosis, erectile dysfunction, decreased libido, and regression (or absence) of secondary sexual characteristics. Hypogonadism
  • Kallman syndrome
Hormones of posterior pituitary: target organs, function, and effects
Hormone Pituitary cell type Target organ Function Decreased production
ADH Supraoptic nuclei of hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
  • Kidneys
  • Arterioles
  • Water reabsorption from kidney
  • Increased blood pressure
  • Vasoconstriction
Diabetes insipidus Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus
Oxytocin Paraventricular nuclei of hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
  • Breast
  • Uterus
Stimulates:
  • Milk ejection
  • Uterine contraction
Causes few symptoms, given limited effects
Pituitary gland and target organs

Pituitary gland and target organs:
The pituitary hormones Pituitary hormones The hypothalamic and pituitary hormones are the most important regulators of the endocrine system. The hypothalamus functions as the coordinating center between the CNS and endocrine system by integrating the signals received from the rest of the brain and releasing appropriate regulatory hormones to the pituitary gland. The pituitary gland then releases its own hormones in response to hypothalamic stimulation. Hypothalamic and Pituitary Hormones help regulate the activity of endocrine glands throughout the body and play an important role in homeostasis.

Image: “Endocrine glands and cells are located throughout the body and play an important role in homeostasis” by Philschatz. License: CC BY 4.0

Clinical Presentation

Hormone deficiencies

Signs and symptoms are dependent on underlying pathology, speed of onset, and severity of hypopituitarism (partial or complete).

  • Anterior pituitary hormone deficiency can be multihormonal or, in some cases, isolated.
    • ↓ Growth hormone (GH deficiency):
      • In adults: lower bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density, muscle atrophy, dyslipidemia, central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
      • In children: short stature, growth retardation
    • ↓ LH and FSH (secondary hypogonadism):
      • Women: ovarian hypofunction (amenorrhea, infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, breast atrophy, ↓ libido)
      • Men: testicular hypofunction (atrophic testes, ↓ libido, ↓ muscle mass)
    • TSH (secondary hypothyroidism):
      • Signs and symptoms: fatigue, dry skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, delayed deep tendon reflexes, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, cold intolerance, bradycardia
      • May have fewer symptoms or symptoms similar to those of primary hypothyroidism
      • In children: growth retardation noted
    • ↓ ACTH (secondary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease):
      • Signs and symptoms: hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, anorexia, vomiting, malaise, weight loss, circulatory collapse
      • No salt wasting/ hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia or volume contraction (aldosterone secretion partially independent from the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland)
      • No hyperpigmentation
    • Prolactin: failure to lactate (cessation of the production of breast milk)
  • Posterior pituitary hormone deficiency:
    • Only ADH deficiency (diabetes insipidus (DI)) manifests clinically.
    • Signs and symptoms: polyuria, polydipsia, hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia, lethargy
    • Symptoms may improve in the setting of ACTH deficiency (↓ ACTH → secretion of inappropriate ADH or SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) due to cortisol deficiency).
  • Panhypopituitarism: decreased secretion of most or all pituitary hormones Pituitary hormones The hypothalamic and pituitary hormones are the most important regulators of the endocrine system. The hypothalamus functions as the coordinating center between the CNS and endocrine system by integrating the signals received from the rest of the brain and releasing appropriate regulatory hormones to the pituitary gland. The pituitary gland then releases its own hormones in response to hypothalamic stimulation. Hypothalamic and Pituitary Hormones

Nonhormonal presenting features

  • Tumors (cause compressive effect on structures):
    • Headache
    • Visual field defects (e.g., bitemporal homonymous hemianopia) and diplopia
  • Sheehan’s syndrome: 
    • Postpartum hemorrhage Postpartum hemorrhage Postpartum hemorrhage is one of the most common and deadly obstetric complications. Since 2017, postpartum hemorrhage has been defined as blood loss greater than 1,000 mL for both cesarean and vaginal deliveries, or excessive blood loss with signs of hemodynamic instability. Postpartum Hemorrhage associated with hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Lethargy, anorexia, inability to lactate
  • Pituitary apoplexy:
    • Sudden excruciating headache
    • Diplopia
    • Acute-onset loss of ACTH causes life-threatening hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension.
  • Genetic diseases and systemic illnesses: Accompanying symptoms depend on the underlying condition or conditions.

Diagnosis

Laboratory tests

ACTH deficiency: 

  • Obtain morning serum cortisol (between 8 and 9 am):
    • Normal: ≥ 18 mcg/dL: sufficient ACTH
    • Low cortisol (≤ 3 mcg/dl) + low serum ACTH: confirms low ACTH
  • If cortisol is indeterminate (4–17 mcg/dl): 
    • Metyrapone test:
      • Logic: Metyrapone blocks conversion of 11-deoxycortisol to cortisol.
      • Oral metyrapone given; 11-deoxycortisol and cortisol levels obtained after 24 hours
      • Intact ACTH reserve would increase 11-deoxycortisol.
      • Low ACTH reserve confirmed if 11-deoxycortisol < 10 mcg/dl and serum cortisol < 7 mcg/dl
    • Cosyntropin stimulation test:
      • Logic: Chronically decreased ACTH leads to adrenal atrophy (low cortisol).
      • Obtain basal ACTH.
      • Administer IM or IV cosyntropin (ACTH).
      • Low cortisol after 30 and 60 minutes indicates adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease.
      • Secondary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease (↓ ACTH reserve) confirmed if low basal ACTH
    • Insulin-induced hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia test:
      • Logic: Insulin causes ↓ glucose, which in turn triggers cortisol secretion in normal circumstances.
      • Inject insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin.
      • Glucose, ACTH, and cortisol are measured in intervals.
      • ACTH deficiency confirmed if inadequate ↑ in cortisol parallel to ACTH at the onset of hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia

GH deficiency: 

  • ↓ Serum insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin-like growth factor-1 (IGF-1) in GH deficiency
  • Provocative tests:
    • GH-releasing hormone ( GHRH GHRH A peptide of 44 amino acids in most species that stimulates the release and synthesis of growth hormone. GHRF (or GRF) is synthesized by neurons in the arcuate nucleus of the hypothalamus. After being released into the pituitary portal circulation, GHRF stimulates gh release by the somatotrophs in the pituitary gland. Hypothalamic and Pituitary Hormones) +/– arginine test: Inadequate increase in GH confirms GH deficiency.
    • Insulin tolerance test: inadequate increase in glucose in GH deficiency

TSH deficiency: 

  • Obtain free thyroxine (T4) and TSH.
  • Deficiency confirmed in:
    • Low or low-normal free T4 (thyroxine) level
    • Low serum TSH level

LH/FSH deficiency:

  • In men: low testosterone, low LH
  • In women: 
    • Normal menstrual cycle Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle is indicative of intact pituitary–ovarian function.
    • Low/normal FSH/LH and low estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle suggest pituitary deficiency.

ADH deficiency: 

  • Water deprivation test and vasopressin stimulation test are used to diagnose DI.
    • Urine osmolality does not increase with serum osmolality.
    • When vasopressin is given, urine osmolality increases.
  • Test also used to differentiate psychogenic polydipsia and nephrogenic DI.

Additional tests

  • Vision field tests look for defects caused by optic nerve compression.
  • Metabolic panel (checking electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes, glucose)
  • Laboratory tests directed at the underlying system illness
  • Imaging: brain MRI or CT scan to detect pituitary tumors/intracranial pathology

Management

Hormone replacement

  • Adrenal insufficiency: 
    • Hydrocortisone replacement (other corticosteroids may be used)
    • Increased dose needed in stress, illness, or surgery
  • TSH deficiency: 
    • L-thyroxine
    • Thyroxine decreases cortisol and can aggravate cortisol deficiency.
    • Do not administer until ACTH deficiency is treated or ACTH reserve is confirmed.
  • GH deficiency:
    • Daily injections of recombinant human GH preparation (in children)
    • Monitor response and adherence with IGF-1.
  • Gonadotropin deficiency (no desire for fertility):
    • Female: estradiol Estradiol The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. Menstrual Cycle + progestin (in postmenopausal women, give only if needed for hot flashes)
    • Male: testosterone replacement
  • Gonadotropin deficiency (desires fertility):
    • Female: ovulation induction with gonadotropins
    • Male: hCG injections
  • ADH deficiency:
    • Desmopressin
    • Low-solute diet, thiazide diuretic

Specific treatments

  • Adrenal crisis:
    • Life-threatening emergency: more common in primary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
    • May occur in secondary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease in settings such as:
      • Pituitary infarction
      • Surgery involving the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland
    • Not associated with decreased volume, but there is decline in vascular tone → hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Do not delay treatment!
    • Give IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids and IV hydrocortisone.
  • Pituitary apoplexy: surgical decompression
  • Pituitary macroadenoma: transsphenoidal surgery for large lesions causing neurologic symptoms
  • Antibiotics for infections
  • Etiology-directed treatments for systemic conditions

Differential Diagnosis

  • Primary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease: inadequate production of adrenocortical hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview ( glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids, mineralocorticoids Mineralocorticoids Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. Mineralocorticoids, and adrenal androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens) caused by damage in the adrenal gland. Suspect this condition, also called Addison’s disease, in hyponatremic patients with hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia (caused by reduced aldosterone). In secondary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease, aldosterone is unaffected.
  • Hyponatremia: A serum sodium concentration of < 135 mEq/L can be due to other endocrine disorders, such as hypocortisolism or hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism caused by adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease. Diagnosis can be made via ACTH or corticotropin-releasing hormone (CRH) stimulation tests.
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism: Secondary causes of hypothyroidism, such as hypopituitarism, can be differentiated from primary thyroid disorders via hormone tests. Low TSH levels are seen in secondary hypothyroidism.
  • DI: condition resulting from decreased secretion of ADH. Patients present with polyuria, thirst, and fatigue. Water deprivation test differentiates DI from primary polydipsia. To determine central versus nephrogenic DI, administer desmopressin; a rise in urine osmolality occurs if central DI (possibly caused by hypopituitarism) is present.
  • Primary hypogonadism: In males, this refers to a decrease in function of the testes (sperm and testosterone production). In females, ovarian insufficiency occurs and manifests as menstrual irregularities. Diagnosis is made by determining levels of pituitary and sex hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview. In males, semen analysis is also performed. Low sex hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview with above normal LH and FSH indicate primary organ failure. 
  • GH deficiency: A decrease in GH can be congenital or acquired. In the pediatric population, presentation can range from microgenitalia to short stature. In adults, less energy, with decreased bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density and reduced lean body mass, are noted. Treatment (growth hormone injections) is necessary for children. In adults, hormone treatment is not routine.
  • Hypoprolactinemia: rarely occurs as an isolated disease. This condition most often occurs because of general anterior pituitary hormone dysfunction. Patients present with inadequate lactation. If milk production is absent, bottle-feeding infants is necessary.
  • Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome: a condition characterized by a deficient release of GnRH by the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus, leading to secondary hypogonadism with low levels of LH, FSH, and GNRH. This can be differentiated from primary hypogonadism, which presents with high levels of GNRH. Pituitary causes of hypogonadism are also present with low levels of gonadotropin.

References

  1. Chapman, I. (2019). Generalized hypopituitarism. Merck Manuals. Retrieved February 5, 2021, from https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/pituitary-disorders/generalized-hypopituitarism
  2. Chung, T., Koch, C., Monson, J. (2018). Hypopituitarism. Endotext. Retrieved February 6, 2021 from https://www.ncbi.nlm.nih.gov/books/NBK278989/
  3. Corenblum, B., Mulinda, J. (2020). Hypopituitarism. Medscape. Retrieved January 26, 2021, from https://emedicine.medscape.com/article/122287-overview#a5
  4. Kim, S. (2015). Diagnosis and Treatment of Hypopituitarism. Endocrinol Metab (Seoul). 30(4): 443–455. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722397/#
  5. Melmed S., Jameson J. (2018). Hypopituitarism. Jameson J, Fauci A. S., Kasper D. L., Hauser S. L., Longo D. L., Loscalzo J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.
  6. Snyder, P. (2019). Causes of hypopituitarism. UpToDate. Retrieved February 6, 2021, from https://www.uptodate.com/contents/causes-of-hypopituitarism
  7. Snyder, P. (2020). Clinical manifestations of hypopituitarism. UpToDate. Retrieved February 6, 2021, from https://www.uptodate.com/contents/clinical-manifestations-of-hypopituitarism
  8. Snyder, P. (2020). Diagnostic testing for hypopituitarism. UpToDate. Retrieved February 6, 2021, from https://www.uptodate.com/contents/diagnostic-testing-for-hypopituitarism

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