Medical School · Year 2 · Endocrine · includes a quiz and discussion video

Lecture 2: Anterior Pituitary Disorders

Unit 2.3: Endocrine System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the clinical features and diagnosis of acromegaly and gigantism
2. Explain hyperprolactinemia causes, presentation, and management
3. Describe Cushing disease and its differentiation from other causes
4. Explain pituitary adenoma classification and management
5. Describe hypopituitarism causes and hormone replacement
6. Explain the evaluation of a pituitary incidentaloma

Lecture Outline

I. Pituitary Adenomas - Overview

Pituitary adenomas are benign tumors arising from anterior pituitary cells, representing the most common sellar pathology and one of the most frequent intracranial tumors. Their clinical significance derives from both hormone hypersecretion (functioning adenomas) and mass effects on surrounding structures (all adenomas).

Epidemiology reveals that pituitary adenomas are remarkably common. Autopsy studies find incidental adenomas in 10-15% of individuals, and approximately 10% of brain MRIs performed for unrelated reasons discover pituitary lesions. Clinically apparent adenomas affect approximately 80-100 per 100,000 population. Peak incidence occurs between ages 30 and 60, with varying gender distribution depending on adenoma type.

Classification occurs by size and by function. Size classification designates tumors smaller than 10 mm as microadenomas, those 10 mm or larger as macroadenomas, and those 40 mm or larger as giant adenomas. Functional classification distinguishes functioning adenomas that secrete excess hormones from non-functioning adenomas that do not cause hormonal syndromes. Prolactinomas are the most common functioning adenoma (40%), followed by non-functioning adenomas (30%), GH-secreting adenomas (15%), ACTH-secreting adenomas (10%), and rare TSH-secreting or gonadotropin-secreting tumors.

Clinical presentation varies by whether the adenoma causes hormone excess, mass effects, or both. Hormone excess syndromes are specific to the hormone type: hyperprolactinemia, acromegaly, Cushing disease. Mass effects manifest when tumors expand beyond the sella turcica. Superior extension compresses the optic chiasm, classically causing bitemporal hemianopia—loss of the temporal visual fields bilaterally, because the crossing fibers from the nasal retina carrying temporal field information are most vulnerable. Further expansion may compress the hypothalamus, causing appetite dysregulation and temperature instability. Lateral extension into the cavernous sinus threatens cranial nerves III, IV, V1, V2, and VI, potentially causing diplopia, ptosis, facial numbness, or facial pain. Large tumors may obstruct the foramen of Monro, causing hydrocephalus. Compression of the normal pituitary tissue causes progressive hypopituitarism.

<image>Panel A: Size classification of pituitary adenomas showing microadenoma (<10mm), macroadenoma (≥10mm), and giant adenoma (≥40mm) with circles to scale. Panel B: Pie chart of adenoma frequency by type with prolactinoma 40%, non-functioning 30%, GH-secreting 15%, ACTH-secreting 10%, and TSH/gonadotroph <5%. Panel C: Coronal section showing macroadenoma mass effects with superior compression of optic chiasm causing bitemporal hemianopia, lateral extension into cavernous sinus affecting CN III, IV, V1, V2, VI. Panel D: MRI comparison of microadenoma versus macroadenoma appearance with clinical presentation features including hormone excess, visual defects, headache, and hypopituitarism.</image>

II. Acromegaly and Gigantism

Growth hormone excess produces dramatically different phenotypes depending on when it occurs relative to epiphyseal fusion. Gigantism results from GH excess before epiphyseal closure during childhood, causing proportional excessive growth and exceptional height. Acromegaly results from GH excess after epiphyseal closure in adults, causing acral and soft tissue overgrowth without increased height because long bones can no longer lengthen.

Etiology is overwhelmingly pituitary in origin. Over 95% of cases result from a GH-secreting pituitary adenoma (somatotroph adenoma). Most are sporadic, but familial syndromes exist including MEN1, Carney complex, and familial isolated pituitary adenoma. Ectopic GHRH secretion (from bronchial carcinoid or pancreatic neuroendocrine tumors) accounts for fewer than 5% of cases—the chronic GHRH stimulation causes somatotroph hyperplasia rather than adenoma. Ectopic GH secretion from non-pituitary tumors is exceptionally rare.

Pathophysiology involves the effects of both GH and its downstream mediator, insulin-like growth factor-1 (IGF-1). GH exerts direct metabolic effects including lipolysis, insulin resistance, and gluconeogenesis stimulation. IGF-1, produced primarily by the liver in response to GH, mediates most growth-promoting effects including cartilage and bone growth, soft tissue proliferation, and organomegaly. The IGF-1 feedback loop that normally restrains GH secretion is disrupted in somatotroph adenomas, which autonomously secrete GH regardless of IGF-1 levels.

Clinical features develop insidiously over years to decades, with an average delay of 7-10 years from symptom onset to diagnosis. Acral changes include enlarged hands (patients notice rings becoming tight), enlarged feet (shoe size increases), and thickened digits. Facial changes include frontal bossing (prominent supraorbital ridges), prognathism (mandibular overgrowth causing underbite), widening of nasal bridge, and macroglossia (tongue enlargement contributing to sleep apnea). Skin changes include thickening, oiliness, hyperhidrosis (excess sweating), and numerous skin tags (often correlating with colonic polyps). Cardiovascular complications include hypertension (50-60%), biventricular hypertrophy, diastolic dysfunction, and cardiomyopathy—cardiovascular disease is the leading cause of mortality. Respiratory complications include both obstructive and central sleep apnea, occurring in 60-80% of patients. Metabolic effects include diabetes mellitus or impaired glucose tolerance (40-50%), insulin resistance, and dyslipidemia. Musculoskeletal complications include arthropathy affecting large joints, carpal tunnel syndrome (70%), and proximal myopathy. Gastrointestinal effects include increased prevalence of colonic polyps and possibly increased colorectal cancer risk, prompting screening colonoscopy recommendations.

<image>Panel A: Patient with acromegaly showing facial features including frontal bossing, prognathism, widened nasal bridge, thick lips, and macroglossia, with enlarged hands compared to normal. Panel B: Cardiovascular and respiratory complications showing biventricular hypertrophy, hypertension, and upper airway obstruction causing obstructive sleep apnea. Panel C: Metabolic and musculoskeletal effects including insulin resistance, diabetes, arthropathy, and carpal tunnel syndrome with colonic polyps requiring screening. Panel D: Disease progression timeline showing years of subtle changes with early clues of tight rings and increased shoe size, plus 2-3x increased mortality if untreated.</image>

III. Acromegaly Diagnosis and Treatment

The diagnosis of acromegaly requires biochemical confirmation because clinical features develop gradually and may be attributed to aging. Treatment aims to normalize GH and IGF-1 levels, control tumor mass, and preserve pituitary function.

Screening begins with measurement of serum IGF-1, the best single screening test. Unlike GH, which is secreted in pulses (making random levels unreliable), IGF-1 has a long half-life and stable serum concentrations, reflecting integrated GH secretion over time. IGF-1 must be interpreted using age- and sex-matched reference ranges because normal levels decline with age. Elevated IGF-1 strongly suggests GH excess but requires confirmatory testing.

Confirmatory testing uses the oral glucose tolerance test (OGTT). After a 75-gram oral glucose load, GH normally suppresses to less than 1 ng/mL (or <0.4 ng/mL using ultrasensitive assays). In acromegaly, GH fails to suppress normally and may even rise paradoxically. The combination of elevated IGF-1 and failure of GH suppression on OGTT confirms the diagnosis of GH excess.

Localization follows biochemical confirmation. Pituitary MRI with gadolinium is the first-line imaging study, identifying the adenoma in over 90% of cases. GH-secreting adenomas are typically macroadenomas at diagnosis. If pituitary MRI is normal despite confirmed biochemical GH excess, consider ectopic GHRH secretion and obtain CT of chest and abdomen to search for carcinoid or pancreatic neuroendocrine tumors.

Treatment goals include normalizing IGF-1 (age-adjusted), achieving GH less than 1 ng/mL (random) or less than 0.4 ng/mL after OGTT, controlling tumor size, relieving mass effects, and preserving pituitary function. Achieving biochemical control significantly reduces mortality toward that of the general population.

Surgical treatment through transsphenoidal adenomectomy is first-line therapy for most patients. An experienced pituitary surgeon achieves biochemical remission in 80-90% of microadenomas but only 40-60% of macroadenomas. Preoperative tumor size and invasiveness (particularly cavernous sinus invasion) are the strongest predictors of surgical success.

Medical therapy is used when surgery is contraindicated, declined, or incomplete. Somatostatin analogs (octreotide LAR, lanreotide, pasireotide LAR) bind somatostatin receptors on tumor cells, inhibiting GH secretion and often shrinking the tumor. They normalize IGF-1 in approximately 50-60% of patients. Pegvisomant, a GH receptor antagonist, blocks GH action peripherally without affecting tumor size; it normalizes IGF-1 in up to 90% of patients and is useful when somatostatin analogs are insufficient. Dopamine agonists (cabergoline) may be effective in adenomas that co-secrete prolactin (common) and are sometimes used as adjunctive therapy.

Radiation therapy (stereotactic radiosurgery or fractionated radiotherapy) is reserved for patients with persistent disease after surgery and medical therapy. Biochemical control often takes years to achieve, and hypopituitarism is a common long-term complication.

<image>Panel A: Diagnostic workup showing IGF-1 measurement with age-adjusted reference ranges as screening, followed by OGTT confirmation with 75g glucose load and GH measurements at baseline through 120 minutes. Panel B: OGTT interpretation comparing normal response (GH suppresses to <1 ng/mL) versus acromegaly (GH fails to suppress), plus pituitary MRI for adenoma localization. Panel C: Transsphenoidal surgery as first-line treatment with success rates of 80-90% for microadenomas and 40-60% for macroadenomas. Panel D: Medical therapy options including somatostatin analogs (50-60% response), pegvisomant (up to 90% IGF-1 normalization), dopamine agonists, and radiation therapy for refractory cases.</image>

IV. Prolactinoma and Hyperprolactinemia

Hyperprolactinemia, elevation of serum prolactin above normal, is among the most common endocrine abnormalities encountered in clinical practice. Understanding the numerous causes is essential because management varies dramatically: dopamine agonists for prolactinomas versus addressing the underlying cause for other etiologies.

Causes of hyperprolactinemia span physiological, pharmacological, pathological, and idiopathic categories. Physiological causes include pregnancy (prolactin rises 10-20 fold by term), lactation, stress, sleep, and nipple stimulation. Pharmacological causes involve dopamine-blocking or dopamine-depleting drugs: antipsychotics (most common medication cause), metoclopramide, domperidone, and certain antidepressants; estrogens; and opioids. Pathological causes include prolactinoma (the most common functioning pituitary adenoma), stalk compression by any sellar or suprasellar mass (disrupting dopamine inhibition), primary hypothyroidism (elevated TRH stimulates prolactin release), and chronic kidney disease (reduced prolactin clearance). Idiopathic hyperprolactinemia exists when no cause is identified.

Prolactinomas are classified by size, with important clinical differences between microadenomas and macroadenomas. Microprolactinomas (<10 mm) are far more common in women, who present earlier with amenorrhea and galactorrhea; prolactin levels typically range from 25-200 ng/mL, generally correlating with tumor size. Macroprolactinomas (≥10 mm) are more common in men, who often present later with mass effects (visual disturbance) because reproductive symptoms are less obvious; prolactin levels frequently exceed 200 ng/mL and may reach thousands. The correlation between prolactin level and tumor size helps distinguish prolactinoma from stalk effect.

Clinical features differ by sex due to the effects of hyperprolactinemia on the reproductive axis. Prolactin inhibits pulsatile GnRH secretion, causing hypogonadism. In women, this manifests as oligomenorrhea or amenorrhea, anovulatory infertility, galactorrhea (present in 30-80%), and, with prolonged hypogonadism, decreased bone density. In men, hyperprolactinemia causes decreased libido, erectile dysfunction, infertility, and occasionally gynecomastia; galactorrhea is uncommon in men. Men often present later with larger tumors because reproductive symptoms are attributed to other causes or minimized.

Diagnosis begins with serum prolactin measurement, repeated to confirm elevation. The hook effect must be considered with very large tumors: extremely high prolactin levels (>10,000 ng/mL) can saturate both capture and detection antibodies in two-site immunoassays, causing a falsely normal or mildly elevated result. If a macroadenoma is found but prolactin is only mildly elevated, request diluted sample re-measurement. The correlation between prolactin level and tumor size is diagnostically useful: prolactin levels of 100-200 ng/mL suggest microprolactinoma or stalk effect; levels over 200 ng/mL (especially >1000) indicate macroprolactinoma.

<image>Panel A: Causes of hyperprolactinemia organized by category including physiological (pregnancy, lactation, sleep), medications (antipsychotics, metoclopramide blocking D2 receptors), and pathological (prolactinoma, stalk compression, hypothyroidism, renal disease). Panel B: Comparison of microprolactinoma (<10mm, female predominance, prolactin <200 ng/mL, reproductive symptoms) versus macroprolactinoma (≥10mm, male predominance, prolactin >200-1000 ng/mL, mass effects). Panel C: Clinical features by sex showing amenorrhea, galactorrhea, infertility, and bone loss in women versus decreased libido, erectile dysfunction, and delayed presentation in men. Panel D: Diagnostic considerations including the hook effect in very large tumors and the correlation between prolactin level and tumor size.</image>

V. Prolactinoma Treatment

The management of prolactinoma differs fundamentally from other pituitary adenomas: medical therapy with dopamine agonists is first-line treatment, not surgery. Dopamine agonists are highly effective at normalizing prolactin and shrinking tumors in most patients.

Medical therapy exploits the unique physiology of lactotrophs, which are under tonic inhibition by dopamine. Dopamine agonists mimic this inhibitory signal, suppressing prolactin synthesis and release while also inducing tumor cell shrinkage through mechanisms that include decreased cell size and induced apoptosis. Cabergoline is the preferred agent due to its twice-weekly dosing, superior efficacy, better tolerability, and lower risk of cardiac valve complications compared to older agents. Bromocriptine is an alternative, typically reserved for patients intolerant of cabergoline or during pregnancy (longer safety record). Both are ergot-derived dopamine agonists acting primarily at D2 receptors.

Response to dopamine agonists is typically excellent. Prolactin levels normalize within weeks in 80-90% of patients. Tumor shrinkage, while slower (occurring over months), is often dramatic—some macroadenomas shrink by 50% or more. Visual field defects may improve rapidly as the tumor shrinks away from the chiasm. Treatment is generally continued long-term, though withdrawal may be attempted after prolonged suppression in selected patients.

Surgical indications for prolactinoma are limited given the efficacy of medical therapy. Surgery may be considered when dopamine agonists cause intolerable side effects (nausea, orthostatic hypotension, mood changes), when tumors are resistant to medical therapy (failure to normalize prolactin or shrink tumor despite adequate doses), when tumor shrinkage causes CSF leak (tumor was sealing a dural defect), when patients prefer a curative attempt over lifelong medication, or when cystic tumors do not respond well to medical therapy.

Special situations require modified approaches. Pregnancy in women with prolactinoma requires careful management. Dopamine agonists restore ovulation, enabling conception. For microprolactinomas, dopamine agonists are typically discontinued when pregnancy is confirmed (tumor enlargement is rare, <5%). For macroprolactinomas, the risk of significant tumor enlargement during pregnancy is higher (15-30%), and some clinicians continue cabergoline; visual fields should be monitored. Resistant prolactinomas (approximately 10%) fail to normalize prolactin or shrink adequately despite high-dose cabergoline; options include surgical debulking, radiation therapy, and temozolomide for aggressive tumors.

Distinguishing stalk effect from prolactinoma is clinically critical because the management differs entirely. The stalk effect (or disconnection hyperprolactinemia) occurs when any mass compresses the pituitary stalk, interrupting dopamine delivery and causing mild hyperprolactinemia (typically <100-150 ng/mL). A non-functioning macroadenoma causing stalk effect will not respond meaningfully to dopamine agonists and requires surgical management for mass effects. In contrast, a macroprolactinoma with prolactin >200-250 ng/mL will shrink dramatically with dopamine agonist therapy.

<image>Panel A: Dopamine agonist mechanism showing D2 receptor binding on lactotroph cells causing decreased prolactin synthesis within weeks and tumor shrinkage over months, with cabergoline (twice weekly, preferred) versus bromocriptine comparison. Panel B: Surgical indications including dopamine agonist intolerance, resistance, CSF leak, patient preference, and cystic tumors not responsive to medical therapy. Panel C: Special situations including pregnancy management (stop dopamine agonists for microprolactinomas, may continue for macroprolactinomas with visual field monitoring) and resistant prolactinoma treatment options. Panel D: Distinguishing stalk effect (prolactin <100 ng/mL, minimal dopamine agonist response, requires surgery) from true prolactinoma (prolactin >200 ng/mL, excellent dopamine agonist response, medical management).</image>

VI. Cushing Disease

Cushing syndrome refers to the clinical manifestations of chronic glucocorticoid excess from any cause. Cushing disease specifically denotes Cushing syndrome caused by an ACTH-secreting pituitary adenoma, representing approximately 70% of endogenous ACTH-dependent cases and the most common cause of endogenous Cushing syndrome overall.

Classification of Cushing syndrome distinguishes ACTH-dependent from ACTH-independent causes. ACTH-dependent causes (80%) include Cushing disease (pituitary adenoma), ectopic ACTH secretion (small cell lung cancer, bronchial carcinoid, other neuroendocrine tumors), and rarely ectopic CRH secretion. In these conditions, ACTH is elevated or inappropriately normal despite high cortisol, and cortisol production responds to ACTH stimulation. ACTH-independent causes (20%) include adrenal adenoma, adrenal carcinoma, bilateral adrenal hyperplasia (primary pigmented nodular adrenal disease, bilateral macronodular adrenal hyperplasia), and exogenous glucocorticoid use (the most common cause of Cushing syndrome overall, though not endogenous). In ACTH-independent causes, ACTH is suppressed because cortisol from the adrenal source feeds back to inhibit the pituitary.

Clinical features of Cushing syndrome result from glucocorticoid effects on multiple organ systems. Body habitus changes include truncal obesity with thin extremities (redistribution of fat), moon facies (facial rounding and plethora), dorsocervical fat pad (buffalo hump), and supraclavicular fat pads. Skin manifestations are particularly useful diagnostically: wide (>1 cm), purple striae (stretch marks over the abdomen, thighs, breasts, and axillae resulting from dermal thinning), facial plethora, easy bruising, thin skin, poor wound healing, and hirsutism in women. Metabolic effects include new-onset diabetes or worsened glycemic control, hypertension (80%), and dyslipidemia. Musculoskeletal effects include proximal myopathy (difficulty rising from a chair, climbing stairs), osteoporosis, and pathologic fractures. Neuropsychiatric manifestations include depression, cognitive impairment, emotional lability, and insomnia. Reproductive effects include menstrual irregularity and decreased libido. Immune suppression increases infection susceptibility.

Cushing disease features specifically relate to the pituitary adenoma. These tumors are usually microadenomas (often <5 mm), making visualization difficult—up to 40% are not clearly seen on MRI. Women are affected more frequently than men (3-4:1). The clinical picture may be milder than ectopic ACTH syndrome because pituitary corticotroph adenomas retain some feedback responsiveness (unlike many ectopic sources).

<image>Panel A: Central body habitus features of Cushing syndrome including moon facies, buffalo hump, supraclavicular fat pads, truncal obesity with thin extremities, wide purple striae (>1cm), thin skin, and easy bruising. Panel B: Metabolic complications showing hyperglycemia, hypertension, dyslipidemia, and musculoskeletal effects including proximal myopathy and osteoporotic compression fractures. Panel C: Neuropsychiatric manifestations (depression, cognitive impairment) and immune suppression with increased infection susceptibility. Panel D: Classification comparison of ACTH-dependent (pituitary 70%, ectopic 30%, elevated ACTH) versus ACTH-independent causes (adrenal adenoma, carcinoma, exogenous steroids, suppressed ACTH).</image>

VII. Cushing Disease Diagnosis and Treatment

The diagnosis of Cushing syndrome requires a systematic approach: first confirm hypercortisolism, then determine whether it is ACTH-dependent or independent, then localize the ACTH source if ACTH-dependent.

Screening tests for hypercortisolism require at least two abnormal tests to establish the diagnosis. The 24-hour urinary free cortisol (UFC) measures total cortisol excretion; values more than three times the upper limit of normal are highly specific. The late-night salivary cortisol exploits the loss of normal circadian variation in Cushing syndrome—cortisol should be at its nadir around midnight, and elevated late-night values suggest autonomous secretion. The 1 mg overnight dexamethasone suppression test assesses feedback: 1 mg dexamethasone taken at 11 PM should suppress morning cortisol to <1.8 μg/dL; failure to suppress suggests autonomous cortisol production.

Establishing ACTH dependence begins with measuring plasma ACTH. Elevated or inappropriately normal ACTH (>10-20 pg/mL) with elevated cortisol indicates ACTH-dependent Cushing syndrome. Suppressed ACTH (<5 pg/mL) indicates ACTH-independent disease (adrenal source).

Differentiating pituitary from ectopic ACTH uses several tests. The high-dose dexamethasone suppression test (8 mg overnight or 2 mg every 6 hours for 48 hours) is based on the principle that pituitary corticotroph adenomas retain some feedback responsiveness while ectopic sources typically do not. Suppression of cortisol by more than 50% suggests pituitary source; no suppression suggests ectopic. The CRH stimulation test stimulates ACTH and cortisol release in pituitary Cushing disease (residual CRH responsiveness) but not in ectopic ACTH syndrome. Neither test is perfectly reliable.

Imaging and localization uses pituitary MRI as the first-line study, identifying an adenoma in approximately 60% of Cushing disease cases; adenomas are often small and may be subtle. Inferior petrosal sinus sampling (IPSS) is the gold standard when MRI is negative or equivocal. Catheters are placed in both inferior petrosal sinuses (which drain the pituitary), and ACTH levels are compared to peripheral blood before and after CRH stimulation. A central-to-peripheral ACTH gradient greater than 2:1 basally or 3:1 after CRH confirms pituitary source with >95% accuracy.

Treatment of Cushing disease prioritizes surgical cure. Transsphenoidal adenomectomy is first-line, achieving remission in 70-90% of microadenomas but lower rates for macroadenomas or invasive tumors. Successful surgery causes temporary cortisol deficiency (because the suppressed normal corticotrophs require time to recover), requiring glucocorticoid replacement for months. Radiation therapy (stereotactic radiosurgery or conventional) is used for surgical failure or recurrence; biochemical remission may take years and hypopituitarism is common. Medical therapy includes steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat) that block adrenal cortisol production; these control hypercortisolism while awaiting definitive therapy or when surgery fails. Bilateral adrenalectomy is a last resort, providing immediate cure but causing permanent adrenal insufficiency requiring lifelong replacement. Post-adrenalectomy, Nelson syndrome may develop—unchecked pituitary tumor growth causing progressive hyperpigmentation (from POMC-derived MSH) and mass effects.

<image>Panel A: Diagnostic screening tests for Cushing syndrome including 24-hour urine free cortisol (>3x ULN specific), late-night salivary cortisol (loss of circadian nadir), and 1mg overnight dexamethasone suppression test (cortisol >1.8 indicates no suppression). Panel B: ACTH-dependent versus ACTH-independent differentiation with high-dose dexamethasone suppression test and CRH stimulation test to distinguish pituitary from ectopic sources. Panel C: Localization using pituitary MRI and inferior petrosal sinus sampling (IPSS) with central-to-peripheral ratio providing >95% accuracy for pituitary source confirmation. Panel D: Treatment algorithm showing transsphenoidal surgery as first-line (70-90% cure for microadenomas), followed by radiation, medical therapy (ketoconazole, metyrapone, osilodrostat), or bilateral adrenalectomy with Nelson syndrome risk.</image>

VIII. Other Functioning Adenomas

Beyond prolactinomas, GH-secreting adenomas, and ACTH-secreting adenomas, rarer functioning pituitary tumors cause distinct clinical syndromes.

TSH-secreting adenomas (TSHomas) represent less than 1% of pituitary adenomas but are clinically important because they cause secondary hyperthyroidism. Patients present with typical hyperthyroid symptoms (palpitations, weight loss, heat intolerance, tremor), but the hallmark laboratory finding is elevated free T4 with inappropriately normal or elevated TSH—normally, elevated T4 should suppress TSH to undetectable levels. This pattern distinguishes TSHoma from primary hyperthyroidism (where TSH is suppressed). The differential diagnosis includes thyroid hormone resistance syndrome, a genetic condition where tissues require higher thyroid hormone levels; distinguishing features include TSHoma patients typically having a visible pituitary adenoma on MRI, elevated alpha subunit levels, and clinical hyperthyroidism (resistance syndrome patients are often clinically euthyroid). Treatment involves transsphenoidal surgery; somatostatin analogs may shrink the tumor and normalize TSH.

Gonadotropin-secreting adenomas (FSH/LH-secreting) are uncommon as clinically functioning tumors, though many "non-functioning" adenomas immunostain positive for gonadotropins or their subunits without causing a clinical syndrome. When clinically significant, men may have elevated FSH or LH levels without the expected clinical response; in premenopausal women, ovarian hyperstimulation syndrome with multiple ovarian cysts can rarely occur from excess FSH. Most commonly, these tumors present with mass effects rather than hormone excess. Treatment is surgical for mass effects.

Silent adenomas are immunohistochemically positive for a hormone but do not cause clinical hormone excess. Silent corticotroph adenomas stain positive for ACTH but do not cause Cushing syndrome; they may behave more aggressively than typical non-functioning adenomas. Silent somatotroph adenomas and silent gonadotroph adenomas similarly produce hormone that is not clinically apparent. The clinical significance lies in potentially more aggressive behavior and the possibility of future hormone hypersecretion.

<image>Panel A: TSH-secreting adenoma (TSHoma) showing paradoxical pattern of elevated free T4 with non-suppressed TSH, hyperthyroid symptoms, pituitary adenoma on MRI, and elevated alpha subunit as diagnostic clue. Panel B: Comparison table distinguishing TSHoma (adenoma present, elevated alpha subunit, clinical hyperthyroidism) from thyroid hormone resistance syndrome (no adenoma, normal alpha subunit, often clinically euthyroid). Panel C: Gonadotroph adenoma features including rare ovarian hyperstimulation in women, typical presentation with mass effects, and immunostaining positive for FSH/LH subunits in many non-functioning adenomas. Panel D: Silent adenomas showing positive immunohistochemical staining for hormones (ACTH, GH) without clinical hormone excess syndrome, with warning about potentially more aggressive behavior.</image>

IX. Non-Functioning Pituitary Adenomas

Non-functioning pituitary adenomas (NFPAs) comprise approximately 25-30% of pituitary adenomas. They are called "non-functioning" because they do not cause a hormone hypersecretion syndrome, though many produce inactive hormones or hormone subunits detectable on immunostaining.

Characteristics of NFPAs relate to their typical late presentation. Because they do not cause early hormone-related symptoms, NFPAs are usually discovered either incidentally on imaging performed for unrelated reasons or when they have grown large enough to cause mass effects. Consequently, most NFPAs at diagnosis are macroadenomas. Histologically, many are of gonadotroph origin, staining positive for FSH, LH, or their alpha subunit, though this does not translate to clinical hormone excess.

Mass effect symptoms dominate the clinical presentation of NFPAs. Visual disturbance from optic chiasm compression is the most common presenting symptom—patients may notice peripheral vision loss, or formal perimetry reveals bitemporal hemianopia. Headache, often described as retro-orbital or temporal, results from dural stretch. Hypopituitarism develops as the tumor compresses normal pituitary tissue; GH and gonadotropin deficiency develop first, with TSH and ACTH deficiency occurring later but being more clinically significant. Mild hyperprolactinemia (typically <100 ng/mL) from stalk compression is common and must be distinguished from a prolactinoma. Cranial nerve palsies occur with lateral extension into the cavernous sinus.

Evaluation of a suspected NFPA includes comprehensive hormonal assessment to exclude a functioning adenoma and identify hypopituitarism. Check prolactin (distinguish from prolactinoma—mild elevation suggests stalk effect), IGF-1 (exclude acromegaly), morning cortisol and ACTH (assess adrenal axis), TSH and free T4 (assess thyroid axis), and FSH, LH, testosterone (men) or estradiol (premenopausal women). Formal visual field testing (automated perimetry) is essential if the tumor approaches or contacts the chiasm. High-quality MRI characterizes tumor size, extension, and relationship to surrounding structures.

Management depends on size and symptoms. Microadenomas (<10 mm) discovered incidentally rarely require intervention. Observation with periodic MRI (typically at 1 year, then less frequently if stable) is standard. Macroadenomas without symptoms may be observed or treated surgically depending on size, proximity to the chiasm, patient factors, and patient preference. Macroadenomas with symptoms (visual field defects, progressive hypopituitarism, intractable headache) require transsphenoidal surgery. Surgical goals include decompression of the optic apparatus and maximal tumor removal while preserving pituitary function. Post-operative surveillance with MRI is essential because recurrence rates range from 12-46%. Radiation therapy may be considered for residual tumor or recurrence.

<image>Panel A: Clinical presentation of non-functioning pituitary adenomas showing visual field testing with bitemporal hemianopia, headache patterns, and hypopituitarism evaluation (prolactin, IGF-1, cortisol/ACTH, TSH/free T4, gonadotropins). Panel B: Stalk effect mechanism showing tumor compressing pituitary stalk, interrupting dopamine delivery, causing mild prolactin elevation (<100 ng/mL) compared to true prolactinoma (>200 ng/mL correlating with size). Panel C: Management algorithm by size showing observation with serial MRI for incidental microadenomas, observation versus surgery for asymptomatic macroadenomas based on chiasm proximity, and transsphenoidal surgery for symptomatic macroadenomas. Panel D: Surgical goals (decompress chiasm, maximal resection, preserve pituitary function) and post-operative surveillance with MRI schedule, 12-46% recurrence rate, and radiation for residual or recurrent disease.</image>

X. Hypopituitarism

Hypopituitarism denotes deficiency of one or more pituitary hormones, ranging from isolated single hormone deficiency to complete pituitary failure (panhypopituitarism). The diverse causes, variable presentations, and critical importance of hormone replacement make hypopituitarism a central topic in endocrinology.

Causes span multiple categories. Tumors are the most common cause, including pituitary adenomas (compression of normal tissue), craniopharyngioma (arising from Rathke's pouch remnants, common in children), and metastases (breast, lung). Vascular causes include Sheehan syndrome (postpartum pituitary necrosis from hypotension during delivery—classically presents with failure to lactate and amenorrhea) and pituitary apoplexy. Inflammatory conditions include lymphocytic hypophysitis (autoimmune, often peripartum), sarcoidosis, and hemochromatosis. Infections (tuberculosis, fungal) are rare. Trauma (head injury) and iatrogenic causes (surgery, radiation) are increasingly recognized. Genetic causes (PROP1, Pit-1, T-PIT mutations) cause combined or isolated pituitary hormone deficiencies.

Order of hormone loss with progressive pituitary damage typically follows a pattern: GH is most sensitive and lost first, followed by FSH/LH, then TSH, then ACTH. Prolactin is usually preserved or elevated (due to stalk effect). However, this order varies, and ACTH deficiency—though typically resistant—is the most life-threatening when it occurs.

Diagnosis requires assessment of each pituitary axis. GH deficiency is assessed by IGF-1 (low IGF-1 with low or normal GH suggests deficiency) and confirmed with stimulation testing (insulin tolerance test is gold standard but risky; GHRH-arginine test is an alternative). ACTH deficiency causes secondary adrenal insufficiency; morning cortisol <3 μg/dL confirms, >18 μg/dL excludes, and intermediate values require ACTH stimulation testing. TSH deficiency causes secondary hypothyroidism with low free T4 and inappropriately low or normal TSH. FSH/LH deficiency causes hypogonadotropic hypogonadism with low testosterone (men) or estradiol (women) and low or inappropriately normal FSH/LH.

Hormone replacement is essential and follows specific principles. Glucocorticoid replacement (hydrocortisone 15-25 mg/day in divided doses, typically two-thirds morning, one-third afternoon) is critical; patients must be educated about stress dosing (doubling or tripling dose during illness, surgery, or major stress) to prevent adrenal crisis. Thyroid hormone (levothyroxine) is given, but critically, cortisol must be replaced before starting thyroid hormone because levothyroxine increases cortisol metabolism and can precipitate adrenal crisis in patients with unrecognized ACTH deficiency. Sex steroid replacement (testosterone in men; estrogen plus progesterone if uterus present in women) addresses gonadotropin deficiency; gonadotropins (hCG, FSH) are used instead when fertility is desired. GH replacement (recombinant human GH) is considered in selected patients for improved body composition, bone density, and quality of life. Desmopressin replaces ADH if diabetes insipidus is present.

<image>Panel A: Causes of hypopituitarism including tumors (pituitary adenoma, craniopharyngioma, metastases), vascular (Sheehan syndrome, apoplexy), inflammatory (lymphocytic hypophysitis, sarcoidosis, hemochromatosis), iatrogenic (surgery, radiation), and genetic mutations (PROP1, Pit-1, T-PIT). Panel B: Order of hormone loss showing GH as most sensitive followed by FSH/LH, TSH, then ACTH (most resistant but most dangerous when deficient), with diagnostic tests for each axis. Panel C: Diagnostic evaluation including IGF-1 and GH stimulation testing, morning cortisol with ACTH stimulation test, free T4 with TSH, and sex steroids with gonadotropins. Panel D: Replacement therapy emphasizing critical principle to replace cortisol before thyroid hormone, with hydrocortisone, levothyroxine, sex steroids or gonadotropins for fertility, GH for selected patients, and desmopressin if diabetes insipidus present.</image>

Summary

Pituitary adenomas are classified by size (micro <10 mm, macro ≥10 mm) and function (hormone-secreting vs non-functioning). Mass effects include bitemporal hemianopia from optic chiasm compression, cranial nerve palsies from cavernous sinus invasion, and hypopituitarism from normal pituitary compression.

Acromegaly results from GH excess in adults, causing acral enlargement, facial changes, cardiovascular disease, sleep apnea, diabetes, and increased mortality. Diagnosis requires elevated IGF-1 and failure to suppress GH on oral glucose tolerance test. Transsphenoidal surgery is first-line; medical therapy includes somatostatin analogs and pegvisomant.

Prolactinoma is the most common functioning adenoma. Unlike other adenomas, medical therapy with dopamine agonists (cabergoline) is first-line, normalizing prolactin and shrinking tumors in 80-90% of patients. Surgery is reserved for dopamine agonist intolerance or resistance.

Cushing disease is ACTH-dependent hypercortisolism from a pituitary adenoma. Diagnosis requires confirming hypercortisolism (UFC, late-night salivary cortisol, DST), establishing ACTH dependence, and localizing the source (MRI, IPSS). Transsphenoidal surgery is first-line treatment.

Non-functioning adenomas present with mass effects and mild hyperprolactinemia (stalk effect). Management ranges from observation (microadenomas) to surgery (symptomatic macroadenomas).

Hypopituitarism follows a typical pattern of hormone loss (GH → FSH/LH → TSH → ACTH), though ACTH deficiency is most dangerous. Critical principle: replace cortisol before thyroid hormone to prevent adrenal crisis.

Key Terms

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