TY - JOUR
T1 - Intraovarian actions of anti-angiogenic agents disrupt periovulatory events during the menstrual cycle in monkeys
AU - Xu, Fuhua
AU - Hazzard, Timothy M.
AU - Evans, Amanda
AU - Charnock-Jones, Stephen
AU - Smith, Stephen
AU - Stouffer, Richard L.
N1 - Funding Information:
This research was supported by grant RF 96020 from the Rockefeller Foundation under the World Health Organization Initiative on Implantation Research and by an NIH Primate Centers grant RR00163. The project did not involve any collaborations with industry, except for the contribution of TNP-470 by Takeda Abbot Pharmaceuticals, Lake Forest, IL.
PY - 2005/4
Y1 - 2005/4
N2 - To determine if anti-angiogenic agents disrupt primate ovarian function, vehicle or a general angiostatic compound (TNP-470), specific antagonists of vascular endothelial growth factor (soluble VEGF receptor-1, sVEGFR-1; anti-VEGF monoclonal antibody, VEGF Ab) and/or an angiopoietin antagonist (Ang-2) were administered to rhesus monkeys: (1) locally via injection into the preovulatory follicle at midcycle or the developing corpus luteum at the midluteal phase; or (2) systemically via subcutaneous injection in the early follicular phase or at midcycle during the natural menstrual cycle. Compared to controls, intrafollicular injection of TNP-470 or sVEGFR-1 decreased circulating progesterone (P) levels in the subsequent luteal phase. Treatment with sVEGFR-1, but not TNP-470, also decreased the incidence of ovulation. Intrafollicular injection of Ang-2 also prevented ovulation, as well as any functional luteal phase. In the absence of elevated P, serum estradiol levels rose to peak levels 11-12 days post-Ang-2 treatment, at which time another large antral follicle was observed on the contralateral (noninjected) ovary. Intraluteal and systemic injection of VEGF antagonists alone or with Ang-2 had minimal effects. Thus, anti-angiogenic factors can act locally in the primate follicle to disrupt the gametogenic (oocyte release) and endocrine (steroid) functions of the ovary. However, further studies are needed to optimize delivery of angiogenic agents before they can be meaningfully evaluated as possible contraceptive agents.
AB - To determine if anti-angiogenic agents disrupt primate ovarian function, vehicle or a general angiostatic compound (TNP-470), specific antagonists of vascular endothelial growth factor (soluble VEGF receptor-1, sVEGFR-1; anti-VEGF monoclonal antibody, VEGF Ab) and/or an angiopoietin antagonist (Ang-2) were administered to rhesus monkeys: (1) locally via injection into the preovulatory follicle at midcycle or the developing corpus luteum at the midluteal phase; or (2) systemically via subcutaneous injection in the early follicular phase or at midcycle during the natural menstrual cycle. Compared to controls, intrafollicular injection of TNP-470 or sVEGFR-1 decreased circulating progesterone (P) levels in the subsequent luteal phase. Treatment with sVEGFR-1, but not TNP-470, also decreased the incidence of ovulation. Intrafollicular injection of Ang-2 also prevented ovulation, as well as any functional luteal phase. In the absence of elevated P, serum estradiol levels rose to peak levels 11-12 days post-Ang-2 treatment, at which time another large antral follicle was observed on the contralateral (noninjected) ovary. Intraluteal and systemic injection of VEGF antagonists alone or with Ang-2 had minimal effects. Thus, anti-angiogenic factors can act locally in the primate follicle to disrupt the gametogenic (oocyte release) and endocrine (steroid) functions of the ovary. However, further studies are needed to optimize delivery of angiogenic agents before they can be meaningfully evaluated as possible contraceptive agents.
KW - Angiopoietin-2
KW - Corpus luteum function
KW - Ovarian disruption
KW - Ovulation
KW - Rhesus monkeys
KW - VEGF
KW - Vascular endothelial growth factor
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U2 - 10.1016/j.contraception.2004.12.017
DO - 10.1016/j.contraception.2004.12.017
M3 - Review article
C2 - 15792643
AN - SCOPUS:15744387584
SN - 0010-7824
VL - 71
SP - 239
EP - 248
JO - Contraception
JF - Contraception
IS - 4
ER -