Endocrine Crash Course for USMLE Step 1
The Hypothalamic-Pituitary Axis (HPA) serves as the master controller of the endocrine system, coordinating hormone release that influences nearly every organ system in the body. This lesson will explore the structure, function, and clinical relevance of the hypothalamus and pituitary gland, the intricate regulatory feedback mechanisms between them, and the diseases that result from their dysfunction. Understanding the HPA is foundational for Step 1 preparation, as its disruptions lead to a wide array of high-yield pathologies that frequently appear on the exam.
The HPA axis is involved in the regulation of stress responses, metabolism, reproductive function, growth and development, lactation, and fluid balance. Key concepts in this lesson include the distinction between anterior and posterior pituitary hormones, the critical role of the hypothalamus in releasing and inhibiting factors, and the consequences of hormone excess or deficiency. We'll also explore how these principles tie into conditions such as prolactinoma, acromegaly, Sheehan syndrome, and craniopharyngioma, all of which require precise pathophysiologic understanding and clinical application.
This system is frequently tested on the USMLE Step 1, not only in straightforward physiology questions but also in complex clinical vignettes involving feedback loops, pharmacologic interventions, and endocrine tumors. By the end of this lesson, you’ll be equipped to analyze and interpret cases involving visual field defects, amenorrhea, hormone resistance, and neuroendocrine tumors. You’ll also apply pharmacological knowledge to manage conditions like GH-secreting tumors and hyperprolactinemia and understand the rationale behind therapeutic choices. Mnemonics and visual tools will help reinforce core ideas and improve recall under timed conditions.
1. Foundations (Physiology / Functional Anatomy)
Hypothalamus: The command center of the endocrine system, situated below the thalamus and forming the floor of the third ventricle. It receives inputs from the brain and peripheral sensors (e.g., temperature, osmolarity, blood pressure), processes them, and coordinates endocrine responses via releasing or inhibitory hormones.
Key releasing/inhibitory hormones and actions:
TRH (Thyrotropin-Releasing Hormone): Stimulates TSH and prolactin; elevated in primary hypothyroidism.
CRH (Corticotropin-Releasing Hormone): Stimulates ACTH release; part of stress axis, elevated in early Cushing disease.
GnRH (Gonadotropin-Releasing Hormone): Stimulates FSH and LH; pulsatile release leads to puberty and fertility, while continuous release suppresses it (basis for GnRH analog therapies).
GHRH (Growth Hormone-Releasing Hormone): Stimulates GH secretion; feedback suppressed by IGF-1.
Dopamine (a.k.a. Prolactin Inhibiting Factor): Tonically inhibits prolactin; inhibition removed by dopamine antagonists (e.g., antipsychotics).
Somatostatin: Inhibits GH and TSH release; elevated in negative feedback or used pharmacologically in GH-secreting tumors.
Pituitary Gland (Hypophysis): Divided into two parts with distinct embryologic origins and functions.
Anterior Pituitary (Adenohypophysis):
Arises from Rathke's pouch (oral ectoderm). It is under direct control of the hypothalamus via the hypophyseal portal system.
Produces six key hormones:
FSH (Follicle-Stimulating Hormone): Stimulates gamete production.
LH (Luteinizing Hormone): Stimulates sex steroid synthesis and ovulation.
ACTH (Adrenocorticotropic Hormone): Stimulates adrenal cortisol production.
TSH (Thyroid-Stimulating Hormone): Stimulates thyroid T3/T4 release.
Prolactin: Promotes lactation; inhibited by dopamine.
GH (Growth Hormone): Stimulates IGF-1 release in liver and growth in tissues.
Functions can be disrupted by tumors or infarction, leading to partial or panhypopituitarism.
Posterior Pituitary (Neurohypophysis):
Derived from neuroectoderm; consists of axonal projections from hypothalamic neurons.
Stores and releases:
ADH (Antidiuretic Hormone/vasopressin): Regulates water balance via V2 receptors in kidneys.
Oxytocin: Triggers uterine contractions and milk let-down reflex.
Dysfunction can cause central diabetes insipidus or uterine atony.
Hypophyseal Portal System:
A vital vascular connection between the hypothalamus and anterior pituitary.
Enables the delivery of releasing/inhibitory hormones directly to target cells without systemic dilution.
Essential for tight hormonal regulation; disruption may impair anterior pituitary signaling (e.g., trauma, surgery).
2. Disease Mechanisms (Pathophysiology)
Pituitary Adenomas (functional or non-functional): These benign tumors arise from the anterior pituitary and can be hormone-secreting (functional) or non-secreting (non-functional). They may cause symptoms due to mass effect (e.g., headaches, visual field defects) or hormonal imbalances.
Prolactinoma (most common type):
Symptoms include galactorrhea (milky nipple discharge), amenorrhea (absence of menstruation), infertility, and decreased libido, especially in women.
Elevated serum prolactin levels suppress GnRH release, leading to decreased secretion of LH and FSH, ultimately causing hypogonadism.
In men, symptoms may include erectile dysfunction, gynecomastia, and visual disturbances due to tumor expansion.
Somatotroph Adenoma (GH-secreting):
In adults, leads to acromegaly: gradual enlargement of hands, feet, jaw (prognathism), coarse facial features, skin tags, and insulin resistance.
In children and adolescents, before epiphyseal plate closure, causes gigantism with tall stature and large extremities.
Often presents with headaches, joint pain, carpal tunnel syndrome, and glucose intolerance.
Corticotroph Adenoma (ACTH-secreting):
Leads to Cushing disease, characterized by hypercortisolism.
Clinical features include moon facies, central obesity, abdominal striae, buffalo hump, easy bruising, hypertension, and glucose intolerance.
Diagnosis involves dexamethasone suppression testing and elevated 24-hour urinary cortisol.
Sheehan Syndrome:
Occurs due to ischemic infarction of the pituitary gland after massive postpartum hemorrhage.
The anterior pituitary is particularly vulnerable due to its blood supply via low-pressure portal vessels.
Common symptoms include inability to lactate, amenorrhea, cold intolerance, fatigue, and loss of pubic/axillary hair.
May present acutely or insidiously months postpartum.
Empty Sella Syndrome:
Radiological finding characterized by an enlarged or partially empty sella turcica, with a flattened or compressed pituitary.
Can be primary (congenital defect in diaphragma sellae) or secondary to surgery, trauma, infarction, or radiation.
Often an incidental finding, but can be associated with hypopituitarism, headache, and CSF rhinorrhea.
More common in obese women with hypertension.
Craniopharyngioma:
Benign, slow-growing tumor of childhood arising from remnants of Rathke’s pouch.
Located in the suprasellar region, often causing compression of the optic chiasm → bitemporal hemianopia.
May also compress the pituitary gland or stalk, resulting in growth failure, delayed puberty, or diabetes insipidus.
Calcifications are common on imaging, and cystic degeneration may occur.
Treatment typically involves surgical resection and/or radiation, though recurrence is possible.
3. Pharmacology
Dopamine Agonists (e.g., cabergoline, bromocriptine):
Mechanism: Stimulate D2 receptors → ↓prolactin.
Use: First-line for prolactinomas.
Somatostatin Analogs (e.g., octreotide, lanreotide):
Mechanism: Mimic somatostatin to suppress GH, TSH, insulin, and glucagon.
Use: Acromegaly, TSH-secreting tumors, carcinoid syndrome.
GH Receptor Antagonist (e.g., pegvisomant):
Blocks peripheral GH receptors → ↓IGF-1.
Use: Refractory acromegaly.
Hydrocortisone or prednisone: For ACTH deficiency or Addison’s disease when adrenal suppression occurs due to pituitary failure.
4. Case Vignettes and Clinical Correlations
Vignette 1: A 30-year-old woman presents with 4 months of amenorrhea and intermittent milky nipple discharge. She also complains of decreased libido. Pregnancy test is negative. Labs reveal elevated prolactin and low FSH/LH. MRI shows a 1.5 cm pituitary mass. → Diagnosis: Prolactinoma. Treat with dopamine agonist.
Vignette 2: A 14-year-old boy has grown rapidly over the past year and complains of headaches and joint pain. He has enlarged hands and feet and a protruding jaw. IGF-1 is elevated. MRI reveals a pituitary mass. → Diagnosis: Somatotroph adenoma (gigantism).
Vignette 3: A woman fails to lactate postpartum, feels chronically fatigued, and reports cold intolerance. Labs show low TSH, cortisol, and prolactin. → Diagnosis: Sheehan syndrome.
Clinical Pearl: Bitemporal hemianopia = optic chiasm compression → think pituitary mass or craniopharyngioma. Visual field testing is critical in suspected cases.
5. Mnemonics
"FLAT PEG" = Anterior pituitary hormones:
FSH, LH, ACTH, TSH (Tropic hormones)
Prolactin, Endorphins, GH (Direct hormones)
"Prolactin is inhibited by Dopamine":
Antipsychotics (dopamine antagonists) like risperidone → hyperprolactinemia.
"Sheehan = Sudden pituitary infarct postpartum".
"Giant = GH tumor in kids", "Acro = GH tumor in adults"
6. Cross-System Integration
Reproductive System:
GnRH → FSH/LH → Estrogen/Testosterone → Secondary sex characteristics
Adrenal Axis:
CRH → ACTH → Cortisol → Glucose metabolism, stress response
Thyroid Regulation:
TRH → TSH → T3/T4 → Basal metabolic rate, growth, CNS development
Feedback Inhibition:
Cortisol, T3/T4, estrogen/testosterone suppress hypothalamus and pituitary to maintain homeostasis