Gonadotropin-releasing hormone agonists

for prevention of chemotherapy-induced ovarian damage:

Prospective randomized study Aboubakr Elnashar

Ahmed Badawy Mohamed El-Ashry

May shahat Egypt

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%

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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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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).

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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?.

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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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Informed consent Sample size Patients were assigned randomly to receive combined GnRHa &chemotherapy or chemotherapy alone.

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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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FSH, LH, E2, P: before starting treatment, then monthly until resuming spontaneous ovulation and menses up to 8 ms after therapy. Serial TVS: at each visit for evaluating the ovary and endometrial thickness. One woman in each group dropped out.

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Outcome measures Return of spontaneous menstruation & ovulation. Hormonal changes: during & after the course of treatment

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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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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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Hormonal changes during the course

of GnRHa/chemotherapy co-treatment

months

mIU/ml ng/ml

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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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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)

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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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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.

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Thank You ABOUBAKR ELNASHAR