Role of GnRH agonist in benign gynaecological disorders

1. Role of GnRH agonist in benign
gynaecological disorders
Aboubakr Elnashar
Benha University Hospital, Egypt
ABOUBAKR ELNASHAR

2. Contents
 GnRHa
Administration
Use in benign gynaecological disorders
1. Endometriosis
2. Uterine fibroids.
3. Thinning agent in DUB (prior to
endometrial ablation).
4. Pituitary down-regulation (in long
protocol of IVF and induction of
ovulation).
5. Adenomyiosis
ABOUBAKR ELNASHAR

3. GNRH AGONISTS
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
100 times more potent than natural LHRH
ABOUBAKR ELNASHAR

4. Mechanism:
After initial agonistic action (flare response),
down-regulation & desensitization of the
pituitary: hypogonadotrophic, hypogonadal
state.
ABOUBAKR ELNASHAR

5. Effects of GnRha
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.
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). ABOUBAKR ELNASHAR

6. The decreased levels of FSH & LH:
1. Arrest of follicular development &
2. 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.
ABOUBAKR ELNASHAR

7.  Administration
• Goserelin:
SC into the anterior abdominal wall every 28 days
+/- 2 days
{1. Best route of absorption and steady dissolution
of depot
2. The trunk area is less sensitive than the thighs:
negligible pain on injection}
ABOUBAKR ELNASHAR

8. Indications in benign gynaecological
disorders
1. Endometriosis.
2. Uterine fibroids.
3. Thinning agent in DUB (prior to endometrial
ablation).
4. Pituitary down-regulation (in long protocol of IVF
and induction of ovulation).
5. Adenomyiosis
6. Before & during chemotherapy for breast cancer
to preserve ovarian functionABOUBAKR ELNASHAR

9. 1. Endometriosis
 GNRHa:
An appropriate therapy of CPP, even in the
absence of laparoscopic confirmation of E,
provided that a detailed evaluation fails to
demonstrate other cause
(ACOG Recommendations Grade (B)
ABOUBAKR ELNASHAR

10. Indications
GnRHa with HT addback
should be considered as 2nd
line treatment:
No response to CHCs or
progestins
Recurrence of symptoms
after initial improvement
(SOGC, 2010)
ABOUBAKR ELNASHAR

11. Types of GnRHa
PriceEPcompanyDoseRouteNamePreparation
750
1550
540
Abbot3.75 mg/4w
11.25 mg/12 w
2.8 ml, 1 ml daily
IM, SC
IM, SC
Lupron
Lucrin
Leuprorelin
500Astrazenica3.6 mgSCZoladexGoserelin
605
266(7syr)
FerringCR: 3.75mg,
0.1mg then 0.05 mg
IM, SCDecapeptylTriptolerin
Sanofi0.5 mg then 0.2 mgNasal, SCsuperfactBuserelin
Pfaizer0.2 mg bidnasalSynarelNafarelin
ABOUBAKR ELNASHAR

12. Side effects:
GnRHa alone: symptoms of estrogen
deficiency
hot flushes
insomnia
Loss of libido,
vaginal dryness,
emotional instability, depression, headache.
loss of BMD, which is not always reversible.
ABOUBAKR ELNASHAR

13. Add-back therapy:
Aim:
To prevent demineralization of bone
& menopausal symptoms.
GnRha should not be given as a
single agent for >6 ms.
GnRHa should not be used for
any length of time in the absence of
HT addback
(SOGC, 2010).
ABOUBAKR ELNASHAR

14. Addbackrationale:There is a threshold serum estrogen concentration that
is low enough that endometriosis is not stimulated but high enough that
hypoestrogenic symptoms are prevented (Barbieri,1992).
This concentration is the same as that achieved with physiologic HT for
menopausal women.
Addback
GnRHa
Oestradiol
Endometriosis symptoms
Menopausal symptoms
ABOUBAKR ELNASHAR

15. •Estrogen-progestagen combination.
Tibilone (livial): 2.5 mg/d.
Bisphosphonates: Etidronate.

ABOUBAKR ELNASHAR

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

17. 2. Uterine fibroids
The main benefits
 Decrease myoma size by about 38% and 41%
after 8 and 12 weeks respectively (hysteroscopic
myomectomy* - proper reconstruction of uterine
anatomy - decrease postoperative adhesions).
 Decrease uterine size by about 32% after 12
weeks(easier surgery). Audebert AJM et al. British Journal of Obstetrics and Gynaecology 1994;
101: Suppl 10, 29–32
Benagiano G et al. Fertility and sterility 1996; 66: 223–229
ABOUBAKR ELNASHAR

18.  Amenorrhoea and endometrial atrophy:
 relief from excessive uterine bleeding.
 restoration of normal Hb concentration.
 detection of stromal fibroids.
 Possibility to schedule operation and avoid emergency.
 Decrease fluid absorption during hysterscopy (due to
decreased endometrial vascularization) & reduce risk of
volume overload.
 Significant decrease blood loss during operation. (No
need for blood transfusion & easier surgery).
 Subjective assessment scores of pain symptoms
decreased by 81% after 8 weeks of treatment.
ABOUBAKR ELNASHAR

19.  Symptom relief
 Patient feels better after 2nd injection.
 Operation can be scheduled to accommodate waiting lists
or to suit patient’s personal plans
 Improvement of patients’ haematological status before surgery
 Reduction of blood loss before and during surgery
 Need for fewer transfusions
 Reduction in size of the fibroids before surgery9
 Simpler and shorter surgery
 Reduction in postoperative recovery time
 Shorter hospital stay
Audebert AJM et al. British Journal of Obstetrics and Gynaecology 1994; 101: Suppl 10, 29–32
Candiani GB et al. Acta Obstet Gynecol Scand. 1990; 69: 413–415
Lumsden MA et al. British Journal of Obstetrics & Gynaecology 1994; 101(5): 438–442ABOUBAKR ELNASHAR

20. Blood picture & reduced uterine volume in
with Fibroids
Pre-treatment 3 months % change 6 months % changes
Haemoglobin ( g/dl) 7.4 13.2 +78* 13.6 +84**
Hematocrit ( %) 26.1 39.8 +52* 40.3 + 55**
Serum Iron ( Mc/dl) 21.7 53.8 +14* 60.8 +180 **
TIBC ( Mc/dl) 394 344 -13* 336 - 15**
Serum Ferritin ( ng/dl) 9.7 17.2 +77* 31.5 +225***
Uterine Volume (ml) 587 298 -49 288 -51**
R.M.Miller et al British journal of Obstetrics and Gynaecology . Feb 1992. Vol 99.
Suppl 7. Pp 37-41
*P < 0.01 compared with treatment
** p = NS compared with 3 month of treatment
***p <0.01 compared with 3 month of treatment
ABOUBAKR ELNASHAR

21. Significant reduction fibroids volume
ZOLADEX 3,6 mg reduces fibroid volume
50
100
150
200
250
300
Immediate surgery group ZOLADEX group
Meanfibroidsize(ml)
Audebert AJM et al. British Journal of Obstetrics and Gynaecology 1994;
101: Suppl 10, 29–32
Benagiano G et al. Fertility and sterility 1996; 66: 223–229
ABOUBAKR ELNASHAR

22. Dose:
Two depots of ‘Zoladex’ given with 4 weeks apart,
then ablation 0-2 weeks after the 2nd depot.
ABOUBAKR ELNASHAR

23. 5. Adenomyosis:
Although adenomyosis & endometriosis are
different diseases, both of them grow& regress in an
oestrogen-dependent fashion (Kitawaki et al,2006).
Adenomyotic tissue contains:
1. Steroid receptors
2. Aromatase& sulphatase enzymes.
Circulating &locally produced oestrogens stimulate
the growth of tissue mediated by the oestrogen
receptors.
ABOUBAKR ELNASHAR

24. To date, there is no agreement on the most
appropriate therapeutic methods for managing
women with uterine adenomyosis who want to
preserve their fertility
(Wang et al, 2009).
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).
ABOUBAKR ELNASHAR

25. GnRHa: in adenomyosis (Wood et al, 2001).
Constant hypoestrogenic state
Amenorrhoea
Control of pain
Uterine shrinkage.
But, pure antiestrogen may offer some advantage in
the treatment of adenomyosis& trials are required to
assess its usefulness.
ABOUBAKR ELNASHAR

26. AI: in Leiomyoma (Parsanezhad et al,2010).
Reduction of leiomyoma& uterine volumes
GnRHa &AI concomitantly: in adenomyiosis (Kimura
et al, 2007).
Assuming aromatase production activity in the
adenomyosis lesion
This stimulated us to undergo this study
GnRHa monthly for 12 w.
ABOUBAKR ELNASHAR

27. 6. GnRHa administration before & during
combination chemotherapy for breast cancer
could preserve post-treatment ovarian function in
women below 40 years
GnRHa:
2 w before the initiation of chemotherapy
Goserelin, 3.6 mg SC
(Zoladex @, Zeneka Pharma International, UK)
ABOUBAKR ELNASHAR

28.  GnRHa before & during combination
chemotherapy for breast cancer:
is feasible, well tolerated
may preserve post-treatment ovarian
function in women below 40 years. .
ABOUBAKR ELNASHAR

29. ABOUBAKR ELNASHAR