Direct protection by a gonadotropin-releasing hormone analog from doxorubicin-induced granulosa cell damage.
OBJECTIVE
Recent clinical applications suggest a beneficial effect of gonadotropin-releasing hormone analog (GnRHa) as a gonadal protector from chemotherapy-induced premature ovarian failure. This study aimed to determine cellular mechanisms involved in the protective action of GnRHa against granulosa cell damage caused by doxorubicin.


METHODS
Granulosa cells were obtained by ultrasound-guided follicular aspiration from patients undergoing in vitro fertilization, and screened for GnRH receptor expression prior to analyses. The cellular function was assessed by measuring the conversion of exogenously supplied androstenedione to estradiol-beta (E2) in response to follicle-stimulating hormone (FSH) (1 microM).


RESULTS
Exposing to doxorubicin for 12 h before FSH stimulation caused a concentration-dependent inhibition of the E2 secretion to a minimum level of 20% of control. When the cells were incubated with a GnRHa for 12 h before and during exposure to doxorubicin, granulosa cells produced an equal level of E2 to that of control cells. The protective action of GnRHa was dose-dependent; a half-maximal effect occurred at 10 nM. Preincubation with GnRHa alone had no effect on FSH-induced E2 production.


CONCLUSIONS
These findings demonstrate that a GnRHa may retard doxorubicin-induced granulosa cell damage, suggesting an additional GnRH activity to protect the gonads during chemotherapy through GnRH receptor-mediated mechanism(s).
Imai
Atsushi
A
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu, Japan. atsushi@cc.gifu-u.ac.jp
Sugiyama
Michiyo
M
Furui
Tatsuro
T
Tamaya
Teruhiko
T
Ohno
Tsukasa
T
D000735:Androstenedione / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D002064:Buserelin / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016729:Leuprolide / Q000494:pharmacology* / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D007987:Gonadotropin-Releasing Hormone; D000735:Androstenedione; D004958:Estradiol; D004317:Doxorubicin; D005640:Follicle Stimulating Hormone; D016729:Leuprolide; D002064:Buserelin