Therapeutic uses of GnRH and GnRH analogues

Question 1

What happens when GnRH is continuously administered?

Answer 1

• Downregulation of gonadotrophin secretion.

Question 2

What happens when GnRH is administered in pulses?

Answer 2

• Upregulation of gonadotrophin secretion

- When stimulation of gonads required

Question 3

Why do we need GnRH analogues?

Answer 3

• GnRH t1/2 = 2-4 mins
• Analogues increase potency and duration.
• Antagonists and agonists.
• Manipulate the HPG axis in clinical practice. IVF, hormone responsive cancers, endometriosis.

Question 4

Which part of the native GnRH is changed in antagonists?

Answer 4

• D amino acid substitutions occur in the receptor binding and activating region. Millar and Newton 2013.

Question 5

What is changed in native GnRH to enhance activity?

Answer 5

D-amino acid substitutions enhance activity with a glycine residue at position 6. Stabilises conformation and enhances activity. Millar and Newton 2013.

Question 6

How to make a GnRH agonist

Answer 6

Straightforward to make agonist

Substitution of Gly by D-amino acids
Replacement of Gly-NH2 by NH2-ethylamide binding to Pro (pos 9/10)

Injectable and avoids proteolytic cleavage. Millar et al 2004.

Question 7

How to make GnRH antagonists.

Answer 7

30 years to make antagonists.

1st generation replaced His & Trp at pos 2 & 3, but low suppressive activity

2nd generation potency increased by D-aa substitution in pos 6 but anaphylaxis by histamine release

3rd generation replaced D-Arg by D-ureidoalkayl aa

Maintains high binding affinity and blocks GnRHR activation.

Millar et al 04

Question 8

What are the clinical uses of native GnRH?

Answer 8

• Diagnosis of impaired gonadal function hypogonadism. Result in decreased sex steroids.
• Used to distinguish between 1 and 2 hypogonadism.
• Delayed puberty.
• Cryptorchidism.

Question 9

What is 1 hypogonadism,.

Answer 9

Arises from gonadal failure.

Question 10

What is 2 hypogonadism.

Answer 10

Abnormalities of HPG axis.

Question 11

Describe the test used to establish hypogonadism.

Answer 11

GnRH is administered intravenously or subcutaneously and plasma LH and FSH are measured at 0, 15, 30, 45 and 60 minutes.

Primary hypogonadism starts in ovary/testes- will have low levels of gonadal steroids along with high levels of LH & FSH and secondary hypogonadism indicates problem in hyp/pituitary axis.

A normalish FHS/LH response suggests that gonadal failure is due to a problem within the ovaries or testes.

If the response is excessive could indicate hypothalamic dysfunction
A reduced FSH/LH response suggests a problem with the hypothalamus or pituitary gland. However very difficult to interpret and if trying to diagnose at puberty then levels of gonadotrophins will depend on stage of puberty.

Question 12

List conditions in which gonadotrophin deficiencies can be seen.

Answer 12

Large pituitary tumors, Endocrine deficiency, Hemochromatosis, Kallmann syndrome, Hyperprolactinemia , Amenorrhea, Anorexia nervosa, Starvation.

Question 13

What is delayed puberty?

Answer 13

• Boys, when testicular growth (volume >4 ml) has not started at 14yrs
• Girls, when breast development is not present at 13yrs or menarche did not occur 15-18 years of age
• Associated with delayed growth, usually boys
  Difficult to distinguish between delayed puberty & HH ⇒ pre-pubertal pituitary is unresponsive

Question 14

What is cryptorchidism?

Answer 14

GnRH required for testes descent and growth of external genitalia in neonatal period.

Question 15

List the clinical uses of GnRH analogues.

Answer 15

IVF 
Dysfunctional uterine bleeding
Precocious puberty 
Hormone-dependent cancers 
Breast cancer
Prostatate cancer
Hirsutism and virilization
Endometriosis

Question 16

How is the HPG axis manipulated in IVF?

Answer 16

• Administration of GnRH agonist. (continuously)
• FSH and LH exogenously administered. Recruits follicles.
• hCG for final maturation - ovulatory process is mimiced and oocytes are retrieved.

Question 17

What are the benefits of using GnRH agonists in IVF?

Answer 17

• Prevent premature LH surge lower cancellation rate
• Improved follicular recruitment  larger no. oocytes recovered (not in all patients)
• Improvement in routine organisation

Question 18

Outline how GnRHa are used in precocious puberty.

Answer 18

• Diagnostic GnRH test
• Administer GnRHa as monthly/3-monthly depot
• Gonadal function is reactivated soon after cessation of treatment

Question 19

What are the issues with precocious puberty?

Answer 19

Problems with PP: inappropriate early biological maturation at variance with psychological immaturity, also significant impairment of final height in untreated central PP.