title: Synergistic effects of antiprogestins and iNOS or aromatase inhibitors on establishment and maintenance of pregnancy.
abstract: Progesterone is known to be involved in many steps in female reproduction including control of implantation and uterine-cervical function during pregnancy. Our studies in rats and guinea pigs indicate that progesterone inhibits uterine contractility and cervical softening during pregnancy. Progesterone levels or actions decline near the end of pregnancy leading to the onset of labor. Treatment with progestin agonists prolongs pregnancy and inhibits cervical softening, whereas treatment with antiprogestins (mifepristone or onapristone) stimulates uterine contractility, cervical softening and premature delivery. Thus the effect of progesterone receptor modulators in the uterus and cervix depend up on the degree of intrinsic agonistic/antagonistic activities. Our recent studies show that progesterone interacts with nitric oxide (NO) to maintain pregnancy and that administration of progesterone antagonists with NO synthase inhibitors act synergistically to stimulate labor. In addition our studies show that combinations of progesterone antagonists with aromatase inhibitors act synergistically to induce labor. Similarly antiprogestins interact with NO synthase or aromatase inhibitors to block implantation through action on the endometrium. These studies suggest new applications for combined therapies of progestin receptor modulators with aromatase inhibitors or agents that modify NO production for contraception, stimulation of labor, estrogen-dependent diseases and improved outcomes in pregnancy.
authors.affiliation: Department of Anatomy and Neurosciences, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1043, USA.
authors.forename: Leili
authors.initials: L
authors.lastname: Shi
authors.forename: Shao-Qing
authors.initials: SQ
authors.lastname: Shi
authors.forename: Randall L
authors.initials: RL
authors.lastname: Given
authors.forename: Helena
authors.initials: H
authors.lastname: von Hertzen
authors.forename: Robert E
authors.initials: RE
authors.lastname: Garfield
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors; D010064:Embryo Implantation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D000077289:Letrozole; D015735:Mifepristone / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009570:Nitriles / Q000494:pharmacology; D011247:Pregnancy; D011372:Progestins / Q000037:antagonists & inhibitors*; D051381:Rats; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D006727:Hormone Antagonists; D009570:Nitriles; D011372:Progestins; D014230:Triazoles; D009569:Nitric Oxide; D015735:Mifepristone; D000077289:Letrozole; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019331:NG-Nitroarginine Methyl Ester