GnRH analogues

Question 1

Continuous low-dose/single high-dose causes

Answer 1

(causes shutdown)
Downregulation of gonadotrophin secretion

• crucial when gonadal inhibition required i.e selective medical hypophysectomy

Question 2

When you deliver GnRH in pulses this switches on the HPG Axis there is an..delete

Answer 2

Upregulation of gonadotrophin secretion

Crucial for when stimulation of gonads required

Question 3

Native GnRH what is it

binds and cellular response - secretion of LH and FSH

Answer 3

Synthetically made GnRH (recombinant) made for clinical application

Question 4

GnRH agonist will have similar effects to the native GnRH however,

Answer 4

this is shortlived.

Question 5

GnRH antagonist, just binds and blocks the receptor so..

(inhibits from the get-go)

Answer 5

no downstream effects.

Question 6

Why GnRH analogues?

Answer 6

• GnRH has a very short half life
• To increase potency & duration of GnRH → analogues created ⇒ agonists or antagonists
• Manipulate the HPG axis in clinical practice- IVF, Hormone responsive cancers, endometriosis

Question 7

These bits are highly conserved in all mammals and most species and why are they important residues for GnRHR binding and activation?

Answer 7

They are important residues for GnRHR binding and activation

Question 8

Mechanisms of action of GnRH and GnRH analogues
SUMMED UP

Answer 8

Question 9

Hypogonadism defined as

Answer 9

impaired gonadal function with resultant decreased sex steroids

Question 10

1° arises from?

Answer 10

arises from gonadal failure

Question 11

To distinguish between 1° & 2° hypogonadism

2° hypogonadism arises from..

Answer 11

Hypogonadism arises from abnormalities of the hypo-pituitary axis.

Question 12

Clinical uses of native GnRH

How is the diagnostic test carried out?

Answer 12

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

Question 13

Clinical uses of GnRH analogues

Answer 13

Delayed puberty
HH
IVF
Dysfunctional uterine bleeding
Precocious puberty
Hormone-dependent cancers
Breast cancer
Prostate cancer
Hirsutism and virilisation
Endometriosis

Question 14

GnRH agonist + gonadotrophins used extensively for

Answer 14

follicle growth stimulation in IVF

Question 15

What is the major benefits of using GnRH agonist + gonadotrophins for follicle growth stimulation in IVF

(x3)

Answer 15

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

Question 16

GnRH agonists and Prostate Cancer

Answer 16

80% of PCa are androgen dependent

GnRH agonist → desensitisation →↓↓ T (chemical castration)

“Flare-effect” results ↑T

Micro-surges of T, LH & FSH with continued use

Co-administer with anti-androgens

Question 17

GnRH agonists & fertility preservation – female cancers

To preserve fertility, we can either

Answer 17

Cryopreserve embryos or MII oocytes after IVF and before chemotherapy

Cryopreserve ovarian tissue for transplantation later

Question 18

Large percentage develop Premature ovarian follicles due to follicular damage in chemo - how?

Answer 18

Chemotherapeutic agents directly attack DNA in dividing and dormant germ cells

Question 19

Limitations of GnRH agonists

Answer 19

Temporary solution - symptoms can return

Side-effects -pseudo-menopause in women (with associated symptoms):
reduced libido, erectile dysfunction, increased LDL / decreased HDL cholesterol, insomnia, headaches

Extra pituitary sites of action? (e.g. oocyte, embryo, uterus) in animals - humans??
GnRHR present on these sites – role in implantation? Inadvertently administered during pregnancy

“Flare effect”

Chronic treatment (>6 months)
Osteoporosis, Heart disease

Question 20

GnRH antagonists & prostate cancer

There are no..

Reduces _______ to castrate levels by day 3

The most commonly used treatment in advanced prostate cancer?

Answer 20

Specifically for Prostate Cancer:

No “flare” or micro-surges.

Reduces testosterone to castrate levels by day 3.

Degarelix –> rapid & sustained reduction in Testo & PSA (prostate specific antigen) routinely used now in advanced prostate cancer.

Question 21

GnRH antagonists advantages

Answer 21

• Rapid action (= rapid pain relief) – 4-6hrs post administered.
• Rapid reversal
• Shorter treatment regime compared to 7-10 days for pituitary down-regulation with agonists.
• No “flare effect”.
• Dose-dependent:
  .Partial pituitary-gonadal inhibition.
  .Can adjust level of hypogonadism as desired.

Question 22

GnRH antagonists disadvantages

Answer 22

• Limited licenses available for wider use.
• More expensive than agonists.
• Need higher dose than agonist 100mg/month versus 3-5mg.
• Competitive inhibitor, therefore less effective over time.