Chapter 32 · Module 1 Visual Summary
Hypothalamic Hormones and Receptor Pharmacology
Releasing hormones, inhibiting hormones, and analog design principles
LH = luteinizing hormone  ·  FSH = follicle-stimulating hormone  ·  TSH = thyroid-stimulating hormone  ·  ACTH = adrenocorticotropic hormone  ·  GH = growth hormone  ·  SSTR = somatostatin receptor subtype  ·  TRH = thyrotropin-releasing hormone  ·  CRH = corticotropin-releasing hormone  ·  HPG/HPT/HPA = hypothalamic-pituitary-gonadal/thyroid/adrenal axes  ·  TIDA = tuberoinfundibular dopaminergic pathway
Hypothalamic Hormones at a Glance
Hormone Receptor / Coupling Pituitary Target Key Clinical Use Analog Examples
GnRH (decapeptide) GnRH-R / Gq Gonadotrophs → LH, FSH Depot agonist: medical castration; antagonist: immediate suppression Leuprolide, goserelin, degarelix, elagolix
TRH (tripeptide) TRH-R / Gq Thyrotrophs → TSH; lactotrophs → prolactin Stimulation test for HPT axis (rarely used now) Protirelin (synthetic TRH)
CRH (41 aa) CRH-R1, R2 / Gs Corticotrophs → ACTH CRH stimulation test for Cushing syndrome differential Ovine CRH (diagnostic)
GHRH (44 aa) GHRH-R / Gs Somatotrophs → GH Tesamorelin for HIV lipodystrophy Sermorelin, tesamorelin
Somatostatin (14 aa) SSTR1–5 / Gi Somatotrophs ↓ GH; also GI, pancreas Acromegaly, carcinoid, VIPoma Octreotide, lanreotide, pasireotide
Dopamine (TIDA pathway) D2R / Gi Lactotrophs ↓ prolactin Prolactinoma treatment Cabergoline, bromocriptine
GnRH Receptor Pharmacology
Pulsatile GnRH
Stimulates LH and FSH
  • 1 pulse every 60–90 min (follicular phase)
  • Activates Gq → PLC-β → IP3/DAG → Ca2+ / PKC
  • Drives LH and FSH exocytosis and gene transcription
  • Basis for pulsatile pump therapy in hypogonadotropic hypogonadism
Continuous GnRH / Depot Agonist
Suppresses LH and FSH
  • Phase 1: PKC-mediated receptor uncoupling (hours)
  • Phase 2: clathrin-independent internalization (days to weeks)
  • Surface receptor density falls 80–95%
  • Testosterone reaches castrate levels within 3–4 weeks
  • Initial testosterone flare: cover with anti-androgen
Somatostatin Receptor Subtypes — Tissue Distribution and Drug Selectivity
SSTR2 and SSTR5
Primary Pituitary Targets
  • Predominate on pituitary somatotrophs
  • SSTR2 dominant on GH-secreting adenomas
  • Octreotide and lanreotide: SSTR2/5-selective
  • Adequate GH suppression in most acromegaly
  • Moderate hyperglycemia risk
SSTR1, 2, 3, 5
Pan-receptor Agonism
  • Pasireotide: high SSTR5 affinity (40x octreotide)
  • Corticotroph adenomas express SSTR5 > SSTR2
  • Used in Cushing disease and SSA-resistant acromegaly
  • Hyperglycemia in 57–73% (SSTR5 suppresses insulin)
  • DPP-4 inhibitors and metformin largely ineffective
GI / Pancreatic SSTRs
Peripheral SSA Effects
  • SSTR2/5 on pancreatic alpha cells ↓ glucagon
  • SSTR5 on beta cells ↓ insulin
  • Suppresses gastrin, VIP, GLP-1, secretin
  • Reduces intestinal motility and splanchnic blood flow
  • Therapeutic in carcinoid, VIPoma, variceal hemorrhage
Analog Design — Solving Native Peptide Limitations
Problem Design Strategy Examples and Outcome
Short half-life (peptidase cleavage) D-amino acid substitution at cleavage sites; C-terminal amidation Leuprolide: D-Leu at position 6 extends t½ from 4 min to 3–8 h. Octreotide: cyclic octapeptide with D-Phe, D-Trp: t½ 1.7–2 h vs 1–3 min native
Frequent injection burden PLGA microsphere depot or subcutaneous autogel Leuprolide LAR: once monthly to once-quarterly IM. Lanreotide autogel: once monthly or every 6–8 weeks SC. Goserelin implant: SC rod 28 or 84 days
No oral bioavailability Non-peptide small molecule design eliminates peptide backbone Elagolix: 57% oral bioavailability, CYP3A4 substrate, dose-dependent partial or complete HPG suppression. Relugolix: 12% oral bioavailability, P-gp / BCRP substrate; no testosterone flare
Drug-Induced Hyperprolactinemia
Drugs That Raise Prolactin
D2R Blockade or TIDA Suppression
  • 1st-gen antipsychotics: haloperidol, chlorpromazine
  • 2nd-gen antipsychotics: risperidone, paliperidone, olanzapine
  • Metoclopramide, domperidone (D2R antagonists)
  • Verapamil (interferes with dopamine release)
  • Chronic opioids (mu receptor suppresses TIDA neurons)
Prolactin-Sparing Antipsychotics
D2R Partial Agonism or Low Affinity
  • Clozapine: low D2R affinity overall
  • Quetiapine: low D2R affinity at pituitary
  • Aripiprazole: partial D2R agonist → lowers prolactin when added to prolactin-elevating agent
Axis Feedback: Three High-Yield Patterns
HPG axis: Low LH/FSH + low sex steroids = central failure (GnRH or gonadotropin deficiency). High LH/FSH + low sex steroids = primary gonadal failure.   •   HPT axis: High TSH + low T4 = primary hypothyroidism. Low TSH + low T4 = central hypothyroidism. TRH elevation in primary hypothyroidism also drives prolactin secretion (galactorrhea).   •   HPA axis: Low ACTH + low cortisol = central or suppressive failure. High ACTH + low cortisol = primary adrenal insufficiency. High ACTH + high cortisol = Cushing disease or ectopic ACTH.