傳統觀念認為腦下垂體抑制劑GnRHa可保護化療或放射治療癌症病患之卵巢功能
新研究顯示此觀念可能是錯誤
Hum Reprod. 2015 Oct 13. pii: dev257. [Epub ahead of print]
GnRH agonist leuprolide acetate does not confer any protection against ovarian damage induced by chemotherapy and radiation in vitro.
Bildik G1,
Akin N1,
Senbabaoglu F1,
Sahin GN1,
Karahuseyinoglu S2,
Ince U3,
Taskiran C4,
Selek U5,
Yakin K6,
Guzel Y7,
Ayhan C7,
Alper E7,
Cetiner M8,
Balaban B7,
Mandel NM9,
Esen T10,
Iwase A11,
Urman B12,
Oktem O13.
Abstract
STUDY QUESTION:
Is there any in vitro evidence for or against ovarian protection by co-administration of a GnRH agonist with chemotherapy in human?
SUMMARY ANSWER:
The co-administration of GnRH agonist leuprolide acetate with cytotoxic chemotherapy agents does not preserve ovarian reserve in vitro.
WHAT IS KNOWN ALREADY:
Randomized controlled trials of the co-administration of gonadotrophin-releasing hormone (GnRH) agonists with adjuvant chemotherapy to preserve ovarian function have shown contradictory results. This fact, together with the lack of a proven molecular mechanism of action for ovarian protection with GnRH agonist (GnRHa) places this approach as a fertility preservation strategy under scrutiny. We therefore aimed in this study to provide in vitro evidence for or against the role of GnRHa in the prevention of chemotherapy-induced damage in human ovary.
STUDY DESIGN, SETTINGS, SIZE AND DURATION:
This translational research study of ex vivo and in vitro models of human ovary and granulosa cells was conducted in a university hospital between 2013 and 2015.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Ovarian cortical pieces (n = 15, age 14-37) and mitotic non-luteinized (COV434 and HGrC1) and non-mitotic luteinized human granulosa cells (HLGC) expressing GnRH receptor were used for the experiments. The samples were treated with cyclophosphamide, cisplatin, paclitaxel, 5-FU, or TAC combination regimen (docetaxel, adriamycin and cyclophosphamide) with and without GnRHa leuprolide acetate for 24 h. DNA damage, apoptosis, follicle reserve, hormone markers of ovarian function and reserve (estradiol (E2), progesterone (P) and anti-mullerian hormone (AMH)) and the expression of anti-apoptotic genes (bcl-2, bcl-xL, bcl-2L2, Mcl-1, BIRC-2 and XIAP) were compared among control, chemotherapy and chemotherapy + GnRHa groups.
MAIN RESULTS AND THE ROLE OF CHANCE:
The greatest magnitude of cytotoxicity was observed in the samples treated with cyclophosphamide, cisplatin and TAC regimen. Exposure to these drugs resulted in DNA damage, apoptosis and massive follicle loss along with a concurrent decline in the steroidogenic activity of the samples. GnRHa co-administered with chemotherapy agents stimulated its receptors and raised intracellular cAMP levels. But it neither activated anti-apoptotic pathways nor prevented follicle loss, DNA damage and apoptosis induced by these drugs.
LIMITATIONS, REASONS FOR CAUTION:
Our findings do not conclusively rule out the possibility that GnRHa may offer protection, if any, through some other mechanisms in vivo.
WIDER IMPLICATIONS OF THE FINDINGS:
GnRH agonist treatment with chemotherapy does not prevent or ameliorate ovarian damage and follicle loss in vitro. These data can be useful when consulting a young patient who may wish to receive GnRH treatment with chemotherapy to protect her ovaries from chemotherapy-induced damage.
STUDY FUNDING/COMPETING INTERESTS:
This study was funded by the School of Medicine and the Graduate School of Health Sciences of Koc University, and the American Hospital Women's Health Center, Comprehensive Cancer Care and Fertility Preservation Programs, Istanbul, Turkey. The authors declare no competing interests.
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