Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: Prospective randomized study

1. Gonadotropin-releasing hormone agonists
for prevention of chemotherapy-induced ovarian damage:
Prospective randomized study
Aboubakr Elnashar
Ahmed Badawy
Mohamed El-Ashry
May shahat
Egypt

2. Infertility is one of the main long-
term consequences of combination
chemotherapy used for treatment of
breast cancer (Glaser; 1994).
The incidence of chemotherapy-
related amenorrhea was 68%
ABOUBAKR ELNASHAR

3. Dividing cells are more sensitive to the
cytotoxic effects of alkylating agents than
are cells at rest
 Inhibition of the pituitary-gonadal axis
reduce the rate of oogenesis
germinal epithelium less susceptible to the
effects of chemotherapy (Shenns; 1993).
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4.  Some studies demonstrated that
GnRHa might inhibit chemotherapy-
induced ovarian follicular depletion
(Glode; 1981).
 Other authors questioned the value
of GnRHa gonadal suppression in
preserving ovarian function against
chemotherapy (Sonmezer & Oktay; 2006).
ABOUBAKR ELNASHAR

5. Based on this controversy,
a prospective RCT was done to
determine
Whether GnRHa administration before &
during combination chemotherapy for
breast cancer could preserve post-
treatment ovarian function in women
below 40 years or not?.
ABOUBAKR ELNASHAR

6. Patients and Methods
 80 patients with:
Unilateral adenocarcinoma of the breast
No metastasis
Modified radical mastectomy or breast-
conserving surgery plus full axillary LN
dissection.
 No radiotherapy as a co-treatment.
 Ages: 18- 40 years
 Premenopausal:
Menstruating normally
FSH< 10 mU/mL.
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7. Informed consent
Sample size
Patients were assigned randomly to
receive
combinedGnRHa &chemotherapy or
chemotherapy alone.
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8. Chemotherapy: FAC regimen
5-Fluorouracil 500 mg/m2 I.V.,
Doxorubicin 500 mg/m2 I.V. and
Cyclophosphamide 500 mg/m2 I.V.)
& then every 6-8 w for 6 cycles.
GnRHa:
2 w before the initiation of chemotherapy
Goserelin, 3.6 mg SC (Zoladex @, Zeneka Pharma
International, UK)
& then every 28 days for 6 months.
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9. FSH, LH, E2, P:
before starting treatment, then
monthly until resuming spontaneous
ovulation and menses up to 8 ms after
therapy.
SerialTVS:
at each visit for evaluating the ovary and
endometrial thickness.
One woman in each group dropped out.
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10. Outcome measures
Return of spontaneous menstruation &
ovulation.
Hormonal changes:
during & after the course of treatment
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11. Study group
(chemotherapy
+GnRHa)
(n=39)
Control group
(chemotherapy)
(n=39)
P
value
Age (ys)
Height (cm)
B wt (kg)
Married patients
Parity
LN excision
Serum FSH (mIU/ml)
Serum LH (mIU/ml)
Serum E2 (pg/ml)
Serum P (ng/ml)
30 ± 3.5
158 ± 12.3
68 ± 3.2
32 (82.0%)
1.9 ± 0.3
25 (64.1%)
4.3 ± 1.1
3.9 ± 1.2
306 ± 21.2
6.7 ± 1.2
29.2 ± 2.9
164 ± 14.5
65 ± 4.2
31 (79.4%)
1.6 ± 0.4
30 (76.9%)
5.7 ± 1.3
4.2 ± 1.4
344 ± 25.6
7.1 ± 1.3
0.76
0.54
0.12
0.91
0.04*
0.21
0.04*
0.14
0.03*
0.12
Patients Characteristics
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12. Study group
(chemotherapy
+GnRHa)
(n=39)
Control group
(chemotherapy)
(n=39)
P value
Menstruating
Ovulating
POF
Serum FSH (mIU/ml)
Serum LH (mIU/ml)
Serum E2 (pg/ml)
Serum P (ng/ml)
35 (89.6%)
27 (69.2%)
4 (11.4%)
8.3 ± 2.1
7.6 ± 2.3
279 ± 23.3
6.3 ± 1.01
13 (33.3%)
10 (25.6%)
21 (66.6%)
15.2 ± 5.3
16.3 ± 2.4
75.43 ± 18.9
3.7 ± 1.2
<0.001*
<0.001*
<0.001*
<0.009*
<0.004*
<0.001*
<0.004*
Outcome 8 months after therapy
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13. Hormonal changes during the course
of GnRHa/chemotherapy co-treatment
months
mIU/ml ng/ml
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14. Discussion
 In 2006, Sonmezer & Oktay stated
that:
In the absence of a prospective RCT
with sufficient power, we do not rely
on ovarian suppression as an effective
means of fertility preservation.
 The present study is a prospective
RCT, with sufficient power
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15. Possible mechanisms of action of GnRHa: (Blumenfeld,
2007)
(a)The hypogonadotropic milieu decreases the
number of primordial follicles entering the
differentiation stage, which is more vulnerable to
chemotherapy
(b)The hypoestrogenic state decreases ovarian
perfusion & delivery of chemotherapy to the
ovaries
(c) Direct effect on the ovary, independet of the
gonadotropin level
(d) Upregulate an intragonadal antiapoptotic molecule such
as sphingosine-1-phosphate
(e) Protect ovarian undd germline stem cells (which
generate de novo primordial follicles)ABOUBAKR ELNASHAR

16. Advantages Disadvantages
1. IVF and
embryo
cryopreservation
Very efficient
Clinically available
•Impractical in the very young,
single woman
•Possibly dangerous in estrogen
aggravated diseases (breast
cancer, SLE)
2. GnRH agonists Simple, inexpensive,
minimal side effects
Ideal when effective
Promising preliminary
results
•Not applicable to radiotherapy
•Not effective in very aggressive
chemotherapy such as BMT
Advantages and disadvantages of fertility-preserving
strategies (Blumenfeld, 2007)
3. Ovum cryopreservation.
4. Ovarian tissue cryopreservation.
Investigational, high technology
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17. Conclusion
 GnRHa before & during
combination chemotherapy for
breast cancer:
is feasible, well tolerated
may preserve post-treatment
ovarian function in women below
40 years.
 Long term studies are required.
ABOUBAKR ELNASHAR

18. Thank You
ABOUBAKR ELNASHAR