Hypothalamus And Pituitary Pathology Flashcards
Answer A
Acromegaly is characterized by the excessive secretion of growth hormone (GH), usually due to a somatotroph pituitary adenoma. The actions of GH are mediated primarily by insulin-like growth factor-1 (IGF-1) from the liver; classic manifestations include bony enlargement of the hands and skull (eg, frontal bossing, jaw malocclusion), arthropathy, cardiomyopathy, and skin thickening. In most cases, initial treatment includes transsphenoidal resection of the tumor. However, if the tumor is unresectable or incompletely resected, the phenotypic manifestations may progress. For these patients, additional medical therapy is indicated.
Octreotide is a long-acting octapeptide somatostatin analogue that has an altered amino acid sequence in the non–receptor binding domain, which makes it more resistant to degradation than native somatostatin. Like somatostatin, octreotide has a broad range of antisecretory actions mediated by membrane receptors. In patients with acromegaly, it inhibits GH secretion and subsequently reduces IGF-1 release, which can mitigate many of the clinical manifestations of the disease. It also exerts an anti-proliferative effect on somatotroph cells and helps reduce residual adenoma size in many patients (Choice E).
(Choices B and D) Pegvisomant is a competitive inhibitor of GH that blocks the binding of GH to its receptor. This drug reduces GH-induced IGF-1 secretion and the subsequent downstream effects but does not alter GH secretion. Adenoma size may remain stable or increase somewhat.
(Choice C) Medical treatment (eg, octreotide) is indicated for patients with incompletely resected somatotroph adenomas because, without treatment, the residual tissue will likely continue to grow and secrete GH, inducing a rise in IGF-1 levels.
Educational objective:
Acromegaly is usually treated with resection of the somatotroph pituitary adenoma, but additional medical therapy is needed for patients with residual tumor. Octreotide is a long-acting somatostatin analogue that inhibits growth hormone secretion and, subsequently, insulin-like growth factor-1 release. It also reduces residual adenoma size in many patients.
Answer A
This patient had typical features of acute pituitary hemorrhage (pituitary apoplexy), including a severe headache, bitemporal hemianopsia (due to compression of the optic chiasm), and ophthalmoplegia (due to compression of the oculomotor nerve [CN III]). Pituitary apoplexy usually occurs in a preexisting pituitary adenoma, as in this patient with chronic headaches and low libido (likely due to hyperprolactinemia). The diagnosis can be confirmed on cross-sectional imaging (MRI scan).
Pituitary apoplexy typically causes loss of all pituitary function; acute loss of ACTH secretion can lead to adrenal crisis (acute central adrenal insufficiency). Cortisol helps maintain vascular tone by potentiating the vasoconstrictive effects of catecholamines (eg, norepinephrine); in the absence of ACTH, the adrenal cortex ceases production of cortisol, leading to severe hypotension and distributive shock. Pituitary apoplexy is a medical emergency that requires urgent treatment with glucocorticoids and neurosurgical consultation.
(Choice B) Hemorrhage into the putamen (basal ganglia) causes neurologic deficits that gradually worsen over minutes to hours. Typical features include contralateral hemiparesis and hemianesthesia due to disruption of the corticospinal and somatosensory tracts. It is most often seen in chronic hypertensive vasculopathy.
(Choice C) Carotid dissection typically presents with unilateral headache, transient vision loss, ptosis, and miosis (partial Horner syndrome). It usually occurs following trauma or can occur spontaneously in patients with chronic hypertension, connective tissue disease, or history of smoking.
(Choice D) Subarachnoid hemorrhage (SAH) due to rupture of a saccular aneurysm near the optic chiasm can present similarly to pituitary apoplexy. However, SAH is usually associated with hypertension due to sympathetic activation, and it is unusual for an aneurysm to cause both bilateral visual field defects (compression of the optic chiasm) and ophthalmoplegia (compression of the CN III or trochlear nerve [CN IV]). This patient’s chronic history of decreased libido followed by acute cardiovascular collapse is more suggestive of a pituitary etiology.
(Choice E) Cavernous sinus thrombosis is most common in patients with underlying thrombophilia, pregnancy, oral contraceptive use, malignancy, or infection. Presenting features include progressively worse headaches, vomiting, seizures, and oculomotor deficits (similar to pituitary mass compression). However, chronically decreased libido, bitemporal hemianopsia, and sudden death from hypotension would be unusual.
Educational objective:
Acute pituitary hemorrhage (pituitary apoplexy) is characterized by severe headache, bitemporal hemianopsia (compression of the optic chiasm), and ophthalmoplegia (compression of the oculomotor nerve [CN III]). It usually occurs in a preexisting pituitary adenoma. Pituitary apoplexy is a medical emergency that requires urgent treatment with glucocorticoids to prevent acute adrenal crisis and circulatory collapse.
A 23-year-old man is brought to the emergency department by paramedics following a motor vehicle accident. He was an unrestrained passenger in the front seat. Several days after hospitalization, his fluid volume and plasma osmolarity are measured and illustrated in the image below (solid line, normal; dotted line, patient).
Which of the following conditions is most likely to cause the findings shown in the image?
A. Acute gastrointestinal hemorrhage
B. Adrenal insufficiency
C. Diabetes insipidus
D. Hypertonic saline infusion
E. Primary polydipsia
Answer C
The figure shows the volume of the intracellular (ICF) and extracellular (ECF) fluid compartments (x-axis) and the osmolarity of the fluid in those compartments (y-axis).
This patient’s recent head trauma is consistent with central diabetes insipidus due to hypothalamic/pituitary damage. The resulting decrease in vasopressin secretion leads to excessive free water excretion by the kidneys, causing hyperosmotic volume contraction. This condition occurs when the loss of free water exceeds the loss of electrolytes, resulting in increased osmolarity and contracted volumes in both the ICF and ECF compartments. Hyperosmotic volume contraction can occur in the setting of diabetes insipidus, decreased fluid intake (dehydration), and with profuse sweating (due to the hypotonic nature of sweat).
(Choice A) Acute gastrointestinal hemorrhage (or diarrhea) would cause an isotonic loss of ECF volume, with no effects on osmolarity or ICF volume. This is referred to as isosmotic volume contraction.
(Choice B) The lack of aldosterone in adrenal insufficiency causes loss of NaCl with ECF volume depletion (hyposmotic volume contraction). The low osmolarity of the ECF results in shifting of free water into the ICF compartment, causing ICF expansion.
(Choice D) Infusion of large amounts of hypertonic saline leads to hypertonic volume expansion. Both the volume and osmolarity of the ECF are increased. The high osmolarity of the ECF leads to shifting of water from the ICF, further increasing the ECF volume.
(Choice E) Primary polydipsia (excessive water consumption) and SIADH (inappropriately high vasopressin levels) both cause retention of free water in the body. This leads to expansion of the ICF compartment and a decrease in the osmolarity of both compartments (hyposmotic volume expansion). Expansion of the ECF compartment is limited in these conditions due to compensatory secretion of aldosterone and natriuretic peptides, which help to normalize the extracellular fluid volume. Thus, affected patients are clinically euvolemic.
Educational objective:
Volume contraction and expansion can be divided into isosmotic, hyposmotic, and hyperosmotic states. Hyperosmotic volume contraction is caused by a loss of free water (with retention of electrolytes). It can occur in patients with diabetes insipidus or as a result of decreased fluid intake/excessive sweating.
Answer D
This patient has symptoms of hypothyroidism (eg, fatigue, weight gain, goiter, thinning of outer eyebrow edges). Her low thyroxine (T4), elevated TSH, and antithyroid peroxidase antibodies are further indicative of primary hypothyroidism from chronic autoimmune (Hashimoto) thyroiditis. In patients with primary hypothyroidism, there is a compensatory increase in hypothalamic thyrotropin-releasing hormone (TRH) production as thyroid hormone levels fall, stimulating increased secretion of TSH by the pituitary.
Prolactin is regulated primarily by the inhibitory effects of dopaminergic neurons from the hypothalamus. However, lactotroph cells express TRH receptors, and TRH stimulates synthesis and release of prolactin. The elevated TRH levels in the pituitary in patients with primary hypothyroidism can therefore increase prolactin secretion and lead to hyperprolactinemia.
In premenopausal women, hyperprolactinemia can cause galactorrhea. Prolactin suppresses GnRH secretion from the hypothalamus, leading to reduced secretion of LH (and to a lesser extent FSH) and subsequent hypogonadism, anovulation, and amenorrhea. Symptoms in men are often nonspecific, but can include infertility, decreased libido, and impotence.
(Choices A and B) The most common cause of primary hypothyroidism is chronic autoimmune (Hashimoto) thyroiditis. Most patients with Hashimoto thyroiditis produce thyroid peroxidase autoantibodies, but it is TRH (not the autoantibodies) that triggers prolactin release.
(Choice C) Antidopaminergic drugs (eg, antipsychotics, metoclopramide) can reduce the inhibitory effect of dopamine on prolactin secretion and lead to hyperprolactinemia, but TSH has little effect on dopamine pathways.
(Choice E) The stimulatory effect of TRH on pituitary lactotrophs is mediated by TRH receptors on lactotroph cells, not by effects on dopaminergic pathways. Overproduction of dopamine would inhibit lactotroph activity.
(Choice F) Effects of the hypothalamic-pituitary-thyroid axis on prolactin secretion are mediated primarily by TRH, not TSH.
Educational objective:
Prolactin production is regulated primarily by inhibitory effects of hypothalamic dopaminergic pathways. However, prolactin secretion is stimulated by thyrotropin-releasing hormone (TRH). In patients with primary hypothyroidism, the increased production of TRH by the hypothalamus can lead to hyperprolactinemia.
Answer C
This patient has bony overgrowth (ie, frontal bossing; enlarged jaw, hands, and feet) consistent with acromegaly. Acromegaly is caused by excessive production of growth hormone (GH) and is most often due to a pituitary somatotroph adenoma. Excess GH both directly and indirectly (via release of insulin-like growth factor 1 from the liver) leads to overgrowth of many tissues, including bone, cartilage, and visceral organs.
In the heart, chronic GH elevation stimulates cardiac growth, causing left ventricular hypertrophy, diastolic dysfunction, and possible heart failure. The joints are also frequently involved in acromegaly, as excessive GH causes hyperplasia of articular chondrocytes and synovial hypertrophy, leading to wear and degeneration of articular cartilage and periarticular bone (hypertrophic arthropathy). Soft tissue involvement is also common and manifests as macroglossia, deepening of the voice (due to laryngeal soft tissue growth), carpal tunnel syndrome, and peripheral neuropathy.
(Choices A and D) Marfan syndrome is an inherited condition caused by a defect in fibrillin-1. Cardiovascular complications include cystic medial degeneration of the aorta (with aneurysmal dilation and dissection), aortic regurgitation, and mitral valve prolapse. However, unlike the bony enlargement in acromegaly, the typical marfanoid habitus is characterized by a tall, slender build and an increased ratio of limb length-to-height.
(Choice B) Ehlers-Danlos syndrome is due to an autosomal recessive defect in lysyl hydroxylase, which leads to defects in connective tissues (eg, fragile, hyperextensible skin). Musculoskeletal manifestations include hypermobile joints, pectus excavatum, and scoliosis. Valvular heart disease is common and can present as bicuspid aortic valve or mitral/tricuspid valve prolapse.
(Choice E) Patients with untreated hypothyroidism can have a pericardial effusion, and also frequently have nonpitting edema (myxedema) due to excessive deposition of mucopolysaccharides and adipogenesis in the dermis and subcutaneous tissues. However, bony enlargement is not characteristic.
Educational objective:
Acromegaly is caused by excessive production of growth hormone, usually due to a pituitary somatotroph adenoma. Musculoskeletal manifestations include bony hypertrophy (eg, frontal bossing; enlarged jaw, hands, and feet) and osteoarthritis. Left ventricular hypertrophy is often common in acromegaly and may progress to heart failure.
Answer C
This patient with sarcoidosis has a hypothalamic and pituitary stalk mass with mass-effect symptoms (eg, headache, bitemporal visual field defects). In combination with the recurrent hypercalcemia (caused by excessive calcitriol formation by activated macrophages) 6 months after the discontinuation of glucocorticoid therapy, this presentation suggests active sarcoidosis with involvement of the hypothalamus (neurosarcoidosis). Although sarcoidosis classically causes noncaseating granulomas involving the lungs, lymph nodes, and skin, granulomas can form in any tissue.
Mass lesions in the hypothalamus or pituitary stalk can disrupt the hypothalamic-pituitary axis by obstructing the hypophyseal portal system. Unlike other pituitary hormones, prolactin release is negatively regulated by dopamine produced in the hypothalamus. Dopamine acts on the dopamine D2 receptors of lactotrophs, the prolactin-producing cells of the pituitary. Disruption of dopaminergic pathways (eg, by an infiltrating sarcoid lesion) in the pituitary stalk leads to loss of inhibition and a subsequent increase in prolactin.
(Choices A, B, and D) Pituitary adenomas can cause excess hormone formation; however, this patient has a hypothalamic mass, not a pituitary adenoma. In contrast to prolactin, other pituitary hormones (ACTH, growth hormone, thyrotropin [TSH], LH, and FSH) are inhibited by hypothalamic lesions because the dominant effect of the hypothalamus on them is stimulatory. Although abruptly discontinuing an oral glucocorticoid can cause adrenal insufficiency with a subsequent increase in ACTH, low blood pressure, hypoglycemia, hyponatremia, and hyperkalemia would be expected. In addition, adrenal insufficiency typically occurs rapidly after glucocorticoid withdrawal (not 6 months later).
(Choice E) Vasopressin is produced in the supraoptic and paraventricular nuclei of the hypothalamus and transported to the posterior pituitary for release. Lesions of the hypothalamus and pituitary stalk can decrease vasopressin levels. Mass lesions in the central nervous system can cause vasopressin secretory dysregulation, leading to the syndrome of inappropriate antidiuretic hormone (SIADH) with euvolemic hyponatremia. However, the normal sodium levels in this patient exclude this syndrome.
Educational objective:
The release of prolactin is under inhibitory control by dopamine secretion from the hypothalamus. Disruption of dopaminergic pathways or blockade of dopamine D2 receptors can cause hyperprolactinemia.
Answer D
This patient likely has the syndrome of inappropriate antidiuretic hormone secretion (SIADH), the most common cause of hyponatremia following subarachnoid hemorrhage (SAH). Antidiuretic hormone (ADH) is normally released by the hypothalamus and posterior pituitary in response to elevated serum osmolality (eg, following water deprivation) or decreased arterial blood volume.
ADH promotes renal water reabsorption, which leads to concentration of the urine and lowering of serum osmolality and serum sodium. Hypothalamic damage following SAH is thought to trigger excessive secretion of ADH, resulting in the classic SIADH features of hypotonicity (ie, low serum osmolarity), hyponatremia, and persistently concentrated urine (ie, high urine osmolality).
In addition to SIADH, hyponatremia after SAH can also be due to cerebral salt wasting (caused by increased secretion of brain natriuretic peptide, which leads to urinary sodium losses) or secondary adrenal insufficiency (eg, decreased cortisol production due to pituitary injury) (Choice E). In both conditions, decreased extracellular fluid volume causes a secondary increase in ADH and worsening hyponatremia.
(Choice A) In primary polydipsia, defective central thirst regulation leads to excessive water intake and hyponatremia. ADH levels are low, rather than high. Primary polydipsia is typically seen with certain psychiatric conditions (eg, schizophrenia) or use of psychotropic medications. It is not commonly associated with SAH.
(Choice B) Impaired renal concentrating ability is seen in diabetes insipidus (DI), which occurs either due to ADH resistance (nephrogenic DI) or decreased ADH production (central DI). DI may follow cerebral injury; however, it does not cause hyponatremia. Rather, DI results in a clinical picture opposite that of SIADH, featuring hypernatremia, increased serum osmolality, and dilute urine (ie, low urine osmolality).
(Choice C) Inadequate dietary intake of sodium is a rare cause of hyponatremia primarily seen in cases of chronic alcohol abuse (eg, beer potomania). SIADH is a more likely cause of hyponatremia in this patient.
Educational objective:
Hyponatremia following cerebral injury (eg, subarachnoid hemorrhage) is most commonly due to the syndrome of inappropriate antidiuretic hormone secretion. Injury to the hypothalamus leads to increased secretion of antidiuretic hormone, which in turn leads to water retention, low serum osmolality, and increased urinary sodium excretion.
Answer B
This patient has diabetes insipidus (DI), a condition that results in the production of large volumes of very dilute urine due to impaired antidiuretic hormone (ADH) activity. DI can be due to deficient ADH production in the brain (central) or resistance to ADH in the kidneys (nephrogenic). Injection of exogenous ADH can help distinguish between central and nephrogenic DI: ADH administration substantially increases urine osmolality in patients with central DI, whereas patients with nephrogenic DI typically have a more limited increase in urine osmolality (<300 mOsm/L increase).
ADH is synthesized by magnocellular neurosecretory cells in the paraventricular and supraoptic nuclei of the hypothalamus. These neurons project axons to the posterior pituitary where axon terminals store large quantities of ADH for later release into the circulation. Injury to the hypothalamus or posterior pituitary (eg, head trauma, transsphenoidal neurosurgery, suprasellar masses) can result in central DI. Damage to the more distal portions of the hypothalamic-hypophyseal tract (ie, below the infundibulum) typically causes transient DI because the cell bodies of the magnocellular neurons remain intact. However, hypothalamic injury results in death of the magnocellular neurons, causing permanent central DI.
(Choice A) The anterior pituitary produces ACTH, TSH, gonadotrophic hormones, prolactin, and growth hormone. Hormone secretion from the anterior pituitary is regulated by substances released from the median eminence into the hypothalamic-hypophyseal portal vessels.
(Choice C) Although head trauma is a frequent cause of central DI, traumatic damage to the kidneys does not result in nephrogenic DI. Furthermore, this patient’s large increase in urine concentration following ADH administration is more suggestive of central DI.
(Choice D) Isolated posterior pituitary damage most often causes transient central DI because the cell bodies of the magnocellular neurons remain intact and can undergo axonal regeneration to allow adequate ADH release into the circulation.
(Choice E) Thalamic nuclei are involved in relaying sensory and motor signals to the cerebral cortex and in regulating alertness and consciousness.
Educational objective:
Injury to the hypothalamus or posterior pituitary (eg, head trauma, transsphenoidal neurosurgery, suprasellar masses) can result in central diabetes insipidus (DI). Damage to the posterior pituitary gland typically causes transient DI, whereas damage to the hypothalamic nuclei often causes permanent DI.
Answer E
This patient is suffering from acute adrenal insufficiency (adrenal crisis) due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis by long-term glucocorticoid therapy. Glucocorticoids suppress the synthesis and release of corticotropin-releasing hormone (CRH) from the hypothalamus and also block its ACTH stimulatory effect on the anterior pituitary. Long-term suppression leads to atrophy of hypothalamic CRH-releasing neurons, pituitary corticotrophic cells, and the adrenal zona reticularis (androgen- producing inner zone) and zona fasciculata (cortisol-producing middle zone).
Chronic glucocorticoid use is characterized by low CRH, ACTH, and cortisol levels that cannot rise in response to stressful situations (eg, infections, surgery) (Choice A). This lack of a stress response can result in relative glucocorticoid deficiency even when the patient’s baseline glucocorticoid regimen is maintained. Because glucocorticoids help maintain normal vascular tone (eg, by increasing norepinephrine, renin, and angiotensin vasoconstrictive activity), glucocorticoid deficiency can precipitate hypotension/shock. In such cases, a higher stress dose is needed to compensate for the increased physiologic demands and prevent the development of adrenal crisis.
(Choice B) Increased levels of CRH and ACTH with decreased cortisol suggest primary adrenal insufficiency, as may be seen in autoimmune adrenalitis or bilateral adrenal hemorrhage/infarction. These patients will also have mineralocorticoid deficiency and are at very high risk for adrenal crisis.
(Choice C) Increased CRH with decreased levels of ACTH and cortisol suggest a pituitary disorder. ACTH is secreted by corticotroph cells of the anterior pituitary; damage to the pituitary by a tumor, infarction, or infection can cause decreased release of ACTH, which in turn leads to decreased cortisol production.
(Choice D) Excessive cortisol production from an autonomous adrenal adenoma suppresses CRH and ACTH production by the hypothalamus and pituitary, respectively.
Educational objective:
Suppression of the hypothalamus-pituitary-adrenal axis by glucocorticoid therapy is the most common cause of adrenal insufficiency. In these patients, adrenal crisis can be precipitated by stressful situations (eg, infections, surgery) if the glucocorticoid dose is not increased appropriately.
Answer D
This patient has common features of acromegaly, including coarsening of facial features (eg, brow protrusion, prognathism), broadening of the hands, and skin involvement (eg, skin tags, hyperhidrosis). Acromegaly is caused by excessive production of growth hormone (GH) and is most often due to a pituitary somatotroph adenoma. Excess GH both directly and indirectly (via release of insulin-like growth factor-1 from the liver) leads to overgrowth of many tissues, including bone, cartilage, and visceral organs.
Acromegaly can affect the joints in both the axial and the appendicular skeleton. Excessive GH causes hyperplasia of articular chondrocytes and synovial hypertrophy, which may appear on x-ray as widening of the joint space. As acromegalic arthropathy continues, there is degeneration of articular cartilage and periarticular bone resembling osteoarthritis.
Complications of the pituitary mass itself include headache, visual field defects (compression of optic chiasm), and abnormalities of other pituitary hormones. Hypogonadism can occur secondary to hyperprolactinemia (from disrupted negative regulation of prolactin secretion) or directly due to compression of pituitary gonadotrophs.
(Choice A) Hereditary hemochromatosis (HH) can cause arthritis due to accumulation of iron in the articular cartilage and synovium. Although HH can also cause central hypogonadism, this patient’s skeletal and facial features are more consistent with acromegaly.
(Choice B) Crystal deposition arthritis typically presents initially with acute inflammatory monarthritis at the first metatarsophalangeal joints and knees (gout), or knees, wrists, shoulders, and elbows (pseudogout [ie, calcium pyrophosphate deposition arthritis]). These disorders would not cause facial changes or hypogonadism.
(Choice C) Sarcoidosis is characterized by the formation of noncaseating granulomas in various tissues. Sarcoid arthropathy often occurs acutely in association with erythema nodosum and hilar adenopathy (Lofgren syndrome); chronic arthritis is less common and usually occurs in patients with significant pulmonary disease.
(Choice E) Rheumatoid arthritis (RA) involves a complex inflammatory response, culminating in an influx of monocytes that differentiate into inflammatory macrophages in the synovium. RA commonly presents with chronic swelling of the metacarpophalangeal joints but does not cause enlargement of the supraorbital ridges or jaw.
Educational objective:
Acromegaly can affect the joints in both the axial and the appendicular skeleton. Excessive growth hormone and insulin-like growth factor-1 cause hyperplasia of articular chondrocytes and synovial hypertrophy, leading to later degeneration of articular cartilage and periarticular bone.
Answer E
This patient with new-onset hyponatremia after drug exposure most likely has the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This condition can be caused by a multitude of drugs, including carbamazepine, cyclophosphamide, and selective serotonin reuptake inhibitors.
Posterior pituitary hormones (eg, ADH, oxytocin) are synthesized within magnocellular neurons found in the supraoptic and paraventricular nuclei of the hypothalamus, with the former primarily producing ADH and the latter oxytocin (Choices D and F). Once translated, these hormones are attached to carrier proteins known as neurophysins. The complexes are packaged into vesicles and travel down axon projections via anterograde transport into the posterior pituitary (neurohypophysis).
At their terminal endings, the axons become neurosecretory terminals known as Herring bodies, temporarily storing secretory vesicles. Pituicytes (glial cells) regulate the permeability of the hypophysial capillaries, facilitating secretion of ADH and oxytocin from the posterior pituitary into the hypophysial vein.
(Choice A) The anterior pituitary (adenohypophysis) is the glandular portion of the pituitary that lies closest to the optic chiasm. It is composed of various hormone-secreting cells, including lactotrophs (prolactin), corticotrophs (ACTH), somatotrophs (growth hormone), thyrotrophs (TSH), and gonadotrophs (FSH, LH).
(Choice B) The intermediate lobe of the pituitary gland is a vestigial region derived from the posterior wall of the Rathke pouch during embryonic development. Although predominantly nonfunctioning, the remainder produces melanocyte-stimulating hormone and endorphins.
(Choice C) The median eminence is a small ridge of hypothalamic tissue that secretes regulatory hormones (both releasing and inhibitory) that modulate the anterior pituitary. These include corticotropin-releasing hormone, gonadotropin releasing hormone, thyrotropin-releasing hormone, and growth hormone–releasing hormone.
Educational objective:
Vasopressin and oxytocin are synthesized and packaged with carrier proteins (neurophysins) within neurons found in the hypothalamus. The hormones are then transported down axonal projections to the posterior pituitary (neurohypophysis), where they are secreted into circulation.
Answer C
This patient has signs of panhypopituitarism with failure of lactation, central hypothyroidism, and adrenal insufficiency. In the setting of a recent delivery, this most likely represents ischemic necrosis of the pituitary gland (Sheehan syndrome). During pregnancy, the pituitary enlarges due to estrogen-induced hyperplasia of the lactotrophs. However, the blood supply to the pituitary does not increase proportionally. As a result, the enlarged pituitary is vulnerable to ischemia in case of systemic hypotension due to peripartum hemorrhage (which this patient likely experienced given her low hemoglobin).
The most common manifestation of Sheehan syndrome is failure of lactation due to prolactin deficiency. It also commonly causes hypocortisolism and hypothyroidism. Manifestations of thyroid deficiency may take a few weeks to develop due to the long circulating half-life of thyroxine (5-7 days) and peripheral conversion of thyroxine (T4) to T3. Cortisol deficiency manifests rapidly, however, with nausea, postural hypotension, fatigue, and weight loss.
(Choice A) Pituitary apoplexy is due to sudden hemorrhage into the pituitary, usually in the setting of a preexisting pituitary adenoma. It usually presents with acute severe headache, ophthalmoplegia, and altered sensorium.
(Choice B) Lymphocytic hypophysitis is the most common inflammatory condition of the pituitary and typically occurs during late pregnancy or the early postpartum period. In contrast to Sheehan syndrome, the presentation is acute with severe headaches and visual field defects.
(Choice D) Primary pituitary cancer is extremely rare, although the pituitary is prone to metastases due to its rich vascular supply. These patients typically present with tumor mass effects (eg, headache, bitemporal hemianopsia).
(Choice E) Non-malignant infiltrative lesions such as sarcoidosis and histiocytosis X mainly involve the suprasellar region, where they compress the hypothalamus and pituitary stalk. This disrupts the normal hypothalamic dopaminergic suppression of prolactin secretion, leading to increased prolactin levels and possible galactorrhea. Central diabetes insipidus may also be seen with resulting hypernatremia.
Educational objective:
High estrogen levels during pregnancy cause enlargement of the pituitary gland without a proportional increase in blood supply. Peripartum hypotension can cause ischemic necrosis of the pituitary leading to panhypopituitarism (Sheehan syndrome). Patients commonly develop failure of lactation due to deficiency of prolactin.
Answer D
This patient most likely has gigantism, a condition caused by hypersecretion of growth hormone (GH) during childhood. GH is a peptide hormone secreted by the anterior pituitary that acts as both a growth promoter and stress hormone (increasing glucose and free fatty acid levels). Although GH has direct effects on target tissue (eg, chondrogenesis, myocyte protein synthesis), its growth-promoting effects are primarily mediated by insulin-like growth factor-1 (IGF-1), which is released from the liver following stimulation of hepatic GH receptors. IGF-1 binds to a specific receptor tyrosine kinase and stimulates cell growth and proliferation in bone, cartilage, skeletal muscle, and other soft tissues.
Gigantism occurs in children and adolescents before fusion of the epiphyseal growth plates, resulting in rapid linear growth along with large hands and feet, thickening of the calvarium, protrusion of the jaw (prognathism), excessive sweating, and oily skin. The adult variant, acromegaly, has no effect on stature because the epiphyseal growth plates have already fused.
(Choices A and B) Klinefelter syndrome is caused by a nondisjunction of sex chromosomes (47,XXY). Patients are phenotypically male with hypogonadism and infertility. Marfan syndrome is caused by a defect in fibrillin-1 and presents with joint hypermobility, increased limb length, and arachnodactyly. These disorders are associated with tall stature but do not exhibit prognathism or bony enlargement of the hands and feet.
(Choice C) Defects in the GH receptor cause Laron dwarfism, characterized by decreased linear growth, high serum GH concentrations, and low levels of circulating IGF-1.
(Choice E) Excessive thyroxine production (ie, hyperthyroidism) presents with weight loss, heat intolerance, and tremor. Sweating is common, but hyperthyroidism in children causes short stature, not accelerated growth.
(Choice F) Circulating levels of IGF-1 are produced primarily in the liver. Although IGF-1 is also produced locally in the hypothalamus to regulate central nervous system activity, this source does not contribute significantly to bone and soft-tissue growth.
(Choice G) Increased pituitary gonadotropin release causes central precocious puberty. This patient has appropriate sexual development for age.
Educational objective:
Gigantism is caused by excess growth hormone (GH) during childhood and is characterized by accelerated linear growth, prognathism, and bony enlargement of the hands and feet. GH excess after closure of the epiphysial growth plates causes acromegaly. GH has direct effects on target tissues and indirect effects mediated by insulin-like growth factor-1 secretion from the liver.
Answer A
This patient has a prolactin-secreting pituitary adenoma (prolactinoma), confirmed with elevated serum prolactin and a pituitary mass visible on MRI. Prolactin can cause hypogonadism (eg, decreased libido, erectile dysfunction, gynecomastia) due to suppression of hypothalamic GnRH production. Mass-effect symptoms of the tumor commonly include headaches and visual field defects due to compression of the optic chiasm.
Unlike most pituitary hormones, which are under positive regulation by releasing hormones (eg, GnRH, TRH) from the hypothalamus, prolactin is primarily under negative regulation by dopaminergic neurons via the pituitary stalk. Dopamine agonists (eg, cabergoline, bromocriptine) are used in patients with prolactinomas to suppress prolactin production and reduce tumor size.
Prolactin levels typically fall significantly within the first 2-3 weeks of therapy (Choices D and E), with a corresponding improvement in hypogonadal symptoms. Although decreased tumor size may not be visible on imaging for several weeks, mass-effect symptoms (eg, visual field defects) usually start to improve much sooner, often within the first several days of treatment (Choices B and C), with eventual normalization in many cases.
Therefore, regardless of the adenoma size and severity of neurologic symptoms, dopamine agonists are the first-line therapy for prolactinoma. Surgery is not needed in most patients; even if surgery is performed, complete resection is often not possible, and recurrence is common, requiring medication therapy.
Educational objective:
Prolactin is under negative regulation by dopaminergic neurons via the pituitary stalk. Dopamine agonists (eg, cabergoline) are used in patients with prolactin-secreting pituitary adenomas (prolactinomas) to suppress prolactin production and reduce tumor size. Benefits are typically seen within the first few weeks of therapy.
