GnRH analogues and addback therapy

GnRH Analogues
&
Addback Therapy

GnRH Agonist
 Produced by Modification of the native
GnRH decapeptide at 6 & 10 positions
 Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-
NH2 -LHRH
 Glp-His-Trp-Ser-Tyr-Ser(But )-Leu-Arg-
Pro-Azgly-NH2 - Goserelin

HISTORY:
 Discovered in 1971
 Introduced for medical use in 1980s
 Most widely used GnRH is leuprolide and
triptorelin.
 Non proprietary names usually end in-relin.

 100 times more potent than natural LHRH
 After initial agonistic action (flare response),
down-regulation & desensitization of the
pituitary: hypogonadotrophic, hypogonadal
state.
Mechanism

Within 12 h of administration:
Flare effect [lasting 24-48 h]
 5 fold increase of FSH
 10 fold rise in LH
 4 fold elevation in E2.
Effects of GnRHAgonist

Continuous administration
 Opposite effects: internalization of the agonist
/receptor complex & decrease in the number
of receptors (down-regulation).
 paradoxical suppression of the pituitary Gnt
synthesis & liberation (desensitization).

The decreased levels of FSH & LH:
 Arrest of follicular development
 Decrease in sex steroid levels to castrate
levels.
 Postmenopausal E2 levels are commonly
reached after 21 days.
The pituitary blockade persist during agonist
treatment but it is reversible after therapy.

LEUPROLIDE
Most commonly used GnRH agonist for
endometriosis
Two dosing options-11.25 mg once every 3 months
3.75mg
One in each month

 Endometriosis.
 Uterine fibroids.
 Thinning agent in DUB (prior to
endometrial ablation).
 Pituitary down-regulation (in long protocol
of IVF and induction of ovulation).
 Adenomyiosis
 Before & during chemotherapy for breast
cancer to preserve ovarian function
Indications

GnRHa
 An appropriate therapy of Chronic pelvic pain,
even in the absence of laparoscopic
confirmation of Endometriosis.
Provided that a detailed evaluation fails to
demonstrate other cause.
(ACOG Recommendations Grade (B)
Endometriosis

GnRHa with Hormone Therapy addback should
be considered as 2nd line treatment
No response to CHCs or progestins
Recurrence of symptoms after initial
improvement
(SOGC, 2010)
Indications

GnRHa alone: Symptoms of estrogen deficiency
 Hot flushes,
 Insomnia,
 Loss of libido,
 Vaginal dryness,
 Emotional instability, depression, headache
 Loss of Bone Mineral Density, which is not
always reversible
Side Effects

Aim: To prevent demineralization of bone &
menopausal symptoms.
GnRha should not be given as a single agent for
>6 months.
GnRHa should not be used for any length of
time in the absence of HT addback
(SOGC, 2010).
Addback Therapy

 There is a threshold serum estrogen
concentration that is
 low enough that endometriosis is not
stimulated
 high enough that hypoestrogenic symptoms
are prevented (Barbieri,1992)
 same as that achieved with physiologic HT
for menopausal women
Add-back Rationale

 GnRHa: Pain relief 85-100% persisting for 6-
12 months after cessation of treatment.
(Winkel et al,2005 )
 GnRHa Vs other hormonal treatment: No
difference with respect to pain relief or
reduction in E deposits (Cochrane library,
2005).
Efficacy

Leuprolide
Buserelin
Nafarelin
Histerelin
Goserelin
Deslorelin
Triptorelin
(Available as daily injections, depot preps, nasal
sprays, implants)
GnRHAgonist Preparations

Hormonal treatment that aims to reduce the proliferation
of endometrial cells is promising, but there is a paucity of
well-designed studies to guide treatment.
There is a strong need to develop pharmacological agents
that provide an efficient outcome (Farquhar et al, 2006).

Commonly employed “add back” regimens
are-
 Low dose combined estrogen and
progestrone
 Estrogen only
 Progestins alone
 Bisphosphonates
 Tibolone
 Raloxifen
Add-Back

 Synthetic steroid
 Estrogenic, progetogenic and androgenic
action
 Prevents loss of bone mineral density
 Prevents vasomotor symptoms
 Dose- 2.5mg for 3-6months with GnRHa
Tibolone

 Synthetic non steroidal drug as an add back
 Afferent to SERM
 Weak estrogenic action at CNS, CVS and
skeleton
 Weak anti estrogenic at reproductive
sites(uterus and breast)
Raloxifen

 Addback with GnRH agonist
 Decreases bone resorption
 Alendronate- 5mg/day
 Improves bone mineral density
Bisphosphonates

 Combined estrogen and progestin add back
therapy protect the bone and prevents hot flushes
and vaginal atrophy

 Ongoing research to identify other uses
 Antagonists with better tolerance need to be
explored
 Injudicious use is not advocated
 Clinicians should be made full aware to
realise the drugs full potential
 When used appropriately with full potential
it can be labelled as “wonder drug”.
Conclusion

GnRH analogues and addback therapy

GnRH analogues and addback therapy

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GnRH analogues and addback therapy