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GnRH-I AND II INDUCED EFFECTS IN
HUMAN OVARIAN CELLS
By
In Sun, Hong
Reproductive and Developmental Science program
Department of Obstetrics and Gynecology
The University of British Columbia
Hypothalamus connecting to the pituitary gland which sends
hormonal signals to the rest of the body
Richard Bertram et al. (2006), Scholarpedia, 1(12):1330
Neural control of reproduction
G. W. HARRIS
(1913–1971)
The identity of Gonadotropin-releasing hormone
Roger Guillemin
Andrew V. Schally
The Nobel Prize in Physiology or Medicine 1977
The identity of GNRH1 was clarified by the 1977 Nobel Laureates Roger Guillemin and
Andrew V. Schally
GnRH regulate gonadotropin and hormone secretion
Nature Neuroscience 7, 1040 - 1047 (2004)
Structure of GnRH and its receptor
J Clin Endocrinol Metab 57: 62, 1983
The identity of GnRH in extra-pituitary tissues
Exp Biol Med (Maywood). 2008 Feb;233(2):123-30. Review
Peter C.K Leung
“GnRH has been implicated as an autocrine regulator in several extra-pituitary tissues,
including the ovary and placenta”
Clinical application of GnRH and its analogues
Gonadal regulation
IVF Therapy
Cancer Therapy
Gonadotropin-releasing hormone agonists in
the treatment of various cancers
Human cancer tissues reported to express GnRH-R
Endocr Rev. 2012 Oct;33(5):784-811
Anti proliferative activity of GnRH
Breast cancer cells
Ovarian cancer cells
Endocrine. 2000 Dec;13(3):297-304.
Endocrinology. 2001 Nov;142(11):4663-72.
Prostate cancer cells
Cancer Res. 1994 Aug 1;54(15):4091-5
Endometrial cancer cells
Eur J Endocrinol. 2002 Jan;146(1):1-14
Anti-metastatic activity of GnRH
Front Neuroendocrinol. 2003 Dec;24(4):279-95.
Int J Oncol. 2008 Aug;33(2):405-13
Int J Cancer. 2002 Jun 1;99(4):505-13
Anti-angiogenic activity of GnRH
Endocrinology. 2010 Oct;151(10):4643-53
Anti-tumor activity through growth factor interfering
Endocr Rev. 2012 Oct;33(5):784-811
Tumor GnRH-R as a Molecular Target for Novel Therapeutic
Strategies in Cancers
Endocr Rev. 2012 Oct;33(5):784-811
Ovarian stimulation with GnRH agonist
during IVF therapy
Estimated risk of Down syndrome according to maternal age
Br J Obstet Gynaecol 1997; 94:387-402.
Regulated fertility services: a commissioning aid –
June 2009, from the Department of Health UK
The decreasing follicle pool and age related decline in fertility
Am J Obstet Gynecol 110:746, 1971
Endocr Rev 18:71, 1997
Ovarian stimulation with GnRH agonist
What is the functional role and molecular mechanism of GnRH-I
and II in human granulosa cells?
The structure and function of ovarian follicles
Mol Cell Endocrinol. 2004 Dec 30;228(1-2):67-78.
After two weeks of sv40 large T antigen transfection
Transfected rapidly
growing colony
Untransfected granulosa cells
The presence of SV40 large T antigen in transfected colonies
The characteristics of primary cultured granulosa cells and
immortalized granulosa cell lines
Anti-proliferative effects of GnRH-I or II on human granulosa cells
Apoptotic effects of GnRH-I or II on human granulosa cells
GnRH I
GnRH II
Antide
GnRH I
Antide
GnRH II
GnRH-I or II exert anti-proliferative effects on human granulosa
cells by interfering with the IGF-I activity
The attenuating effects of GnRH-I or II on the activity of IGF-I in
granulosa cells apoptosis
GnRH-I or II interfere with IGF-I induced Akt signaling pathways
GnRH-I or II interfere with IGF-I induced Akt signaling pathways
Two possible mechanisms of GnRH-I or II induced anti-proliferative
effects in human granulosa cells
1
GnRH-I, II
Caspase-dependent pathway
Apoptosis
2
GnRH-I, II
IGF-I
Akt
IGF-I activity
Acknowledgements:
Dr. Leung’s Lab
Dr. Peter CK Leung
Dr. Christian Klausen
Jordan Cheng
Raymond Lau
Kelvin So
William Chang
Mya Zhang