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The Pharmacobiology of GnRH/LHRH Agonists and Antagonists. Franklin D. Gaylis, MD, FACS Chairman, Evidence Based Medical Group of San Diego San Diego, California. Hormonal Influences on Prostate Cancer. Hypothalamus. LHRH. GnRH Receptor. Testes. Pituitary. Leydig Cells. FSH. LH.

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the pharmacobiology of gnrh lhrh agonists and antagonists

The Pharmacobiology of GnRH/LHRH Agonists and Antagonists

Franklin D. Gaylis, MD, FACS

Chairman, Evidence Based Medical Group of San Diego

San Diego, California

hormonal influences on prostate cancer
Hormonal Influences on Prostate Cancer

Hypothalamus

LHRH

GnRHReceptor

Testes

Pituitary

LeydigCells

FSH

LH

SertoliCells

FSH

OtherTargetTissues

DHT Receptor

Testosterone

Prostate

Brawer MK. Rev Urol. 2001;3:S1. Pending permission.

evolution of hormone blockade
Evolution of Hormone Blockade

LHRHAgonist + Anti-androgen (CAB)

LHRHAgonist

GnRHAntagonists

Orchiectomy

DES

<1940

1940

1985

1989

2002–03

examples of lhrh agonists and antagonists
Agonists

Leuprolide

Goserelin

Buserelin

Antagonists

Abarelix

Cetrorelix

Ganirelix

Antide

Teverelix

ORG-30850

A-75998

Examples of LHRH Agonists and Antagonists
lhrh superagonists
LHRH Superagonists

H

N

H

GLY

GLY

PYROGLU

HIS

TRP

SER

TYR

LEU

ARG

PRO

6

10

1

2

3

4

5

7

8

9

d-amino acid substitutions

Adapted from Schally AV. Peptides. 1999;20:1247. With permission from Elsevier Science and AlphaMed Press.

lhrh agonists mechanism of action
LHRH Agonists:Mechanism of Action
  • Bind to same site in the GnRH receptor as the naturally occurring LHRH
  • Stimulate production of LH andFSH initially
  • Eventually “exhaust” or internalize the GnRH receptor, thereby suppressing LH production
gnrh antagonists
GnRH Antagonists

H

N

H

TYR

GLY

ARG

PYROGLU

HIS

TRP

LEU

PRO

GLY

SER

8

1

2

3

5

6

9

10

7

4

These residues replaced by d-amino acid in most antagonists

Areas of key differences among antagonists

lhrh agonists and antagonists structural differences
LHRH Agonists and Antagonists:Structural Differences

LHRHGlu - His - Trp - Ser - Tyr - Gly - Leu - Arg - Pro - GlyHuman Genome

LHRHpGlu - His - Trp - Ser - Tyr - Gly - Leu - Arg - Pro - Gly - NH2 Modified Agonist

LeuprolidepGlu- His - Trp - Ser - Tyr -Dleu- Leu - Arg - Pro -NH - EtSuperagonist

AbarelixAcDNal-DClPhe-Dpal- Ser -NMTyr - DAsn- Leu -Ilys- Pro -DAla - NH2Antagonist

Natural building blocks

Synthetic building blocks

gnrh antagonists mechanism of action
GnRH Antagonists:Mechanism of Action
  • Bind to pituitary GnRH receptors, causing immediate suppression of LH and FSH
  • Turn off GnRH receptor by immediately and persistently blocking it, thus avoiding testosterone surge and “clinical flare”
obstacles in the development of the gnrh antagonists
Obstacles in the Development of the GnRH Antagonists
  • Insufficient potency
  • Lack of solubility
  • Unacceptable histamine release
  • Limitations with sustained release formulations
abarelix
Abarelix
  • First GnRH antagonist to progress through clinical trials for prostate cancer
  • Synthetic decapeptide GnRH antagonist that selectively binds to and immediately blocks the GnRH receptor
  • Suppresses both LH and FSH secretion
  • Sustained-release formulation
agonists vs antagonists clinical effects
Agonists

Initial stimulation of LH production testosterone surge

Potential for testosterone surge and “clinical flare”

May cause temporary rise in PSA levels

Antagonists

Immediate, complete suppression of LH and testosterone

PSA suppressed more quickly

No risk of testosterone surge

Agonists vs Antagonists:Clinical Effects
median testosterone levels
Median Testosterone Levels

Study 149-98-03 Patients Through Day 85

Abarelix

Leuprolide+bicalutamide

600

600

500

500

400

400

T Level (ng/dL)

T Level (ng/dL)

300

300

200

200

100

100

0

0

0

20

40

60

80

100

0

20

40

60

80

100

Study Day

Study Day

Adapted from Trachtenberg J, et al. J Urol. 2002;167:1670.With permission from Lippincott, Williams, & Wilkins. www.lww.com

significance of fsh suppression
Significance of FSH Suppression
  • A preclinical study was conducted to characterize the expression of the follicle-stimulating hormone receptor (FSHR) in androgen-independentprostate cancer cell lines and human malignant prostate tissues.
  • Results suggest that:

The FSHR expressed on these cancer cells is biologically active

FSH can stimulate proliferation of androgen-resistant prostate cancer cells in the absenceof androgen.

  • FSH and/or its receptor may be potential targets in human prostate cancer.
fsh levels after gnrh antagonist and after gnrh agonist anti androgen
FSH Levels After GnRH Antagonist and After GnRH Agonist ± Anti-androgen

40

GnRH agonist ± anti-androgen

30

GnRH antagonist(abarelix depot)

Median FSH Level (IU/L)

20

10

0

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

Time (Days)

Garnick MB, et al. Mol Urol. 2000;4:275.

potential applications for gnrh antagonists
Potential Applications forGnRH Antagonists
  • Advanced disease where testosterone surge and clinical flare might be dangerous
  • Short periods of treatment, eg, downsizing prior to brachytherapy
  • Intermittent therapy
  • Future research into the possible role of FSH and FSH receptors
summary
Summary
  • Discovery of the decapeptide structure of LHRH in 1970s led to development of compounds that would effectively create androgen suppression, utilizing the LHRH structure
  • GnRH receptor ultimately receives and mediates the primary stimulatory input to gonadotropes
summary19
Summary
  • LHRH agonists
    • Initial treatment stimulates LH and FSH release
      • Increased LH leads to testosterone surge and clinical flare
    • Chronic administration
      • Causes downregulation of GnRH receptor and inhibition of LH
      • Does not suppress FSH
  • GnRH antagonists bind to, and persistently block, GnRH receptors
    • Antagonists shut the receptor off
    • Immediately suppress LH and FSH production
    • Results in immediate reduction of testosterone to castrate levels
    • Avoid testosterone surge and “clinical flare”