Flavonoids are common dietary constituents which may have a significant impact on estrogen-mediated aspects of fertility. In vitro experiments indicate that flavonoids are capable of altering estrogen action both directly, through interactions with estrogen receptors, and indirectly, through changes in the rate of estrogen biosynthesis. This study will test the hypothesis that dietary flavonoids can directly and/or indirectly alter estrogen action in vivo. The animal model chosen for these experiments is the albino rat. The flavonoids chosen for investigation are representative of the opposite ends of the spectrum of estrogen receptor affinity to inhibition of estrogen biosynthesis. The proposed experiments are designed to test the effects of consumption of normal dietary levels of flavonoids on estrogen-responsive tissues and reproductive processes in the reproductive tract and central nervous system. The results of these experiments will provide the framework for evaluating the potential reproductive hazards of particular diets. Three hypotheses of the effects if flavonoid consumption will be tested: 1) Dietary flavonoids can directly affect estrogen action by mimicking and/or antagonizing the effects of estrogen on the uterus, pituitary, and hypothalamus 2) Dietary flavonoids can indirectly affect estrogen action by altering the rate of aromatization of androgen to estrogen in the ovary and the brain 3) Dietary flavonoids can disrupt normal reproductive function by altering estrogen dependent reproductive processes. Direct effects on estrogen action will be tested in specific experiments which examine the effects of flavonoid consumption by immature rats on uterine growth, positive feedback, and feeding activity and on the activation of estrogen receptors and induction of progestin receptors in the uterus, hypothalamus, and pituitary. Indirect effects on estrogen action will be tested in experiments which examine the effects of flavonoid administration on estrogen biosynthesis in ovarian perifusates and the effects of flavonoid consumption by castrated rats on aromatase activity in the hypothalamus. Finally, the potential for disruption of normal reproductive function will be tested by examining the effects of flavonoid consumption on sexual differentiation sexual maturation, and the maintenance of normal estrous cycles.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Whitten, Patricia L; Patisaul, Heather B; Young, Larry J (2002) Neurobehavioral actions of coumestrol and related isoflavonoids in rodents. Neurotoxicol Teratol 24:47-54
Whitten, P L; Lewis, C; Russell, E et al. (1995) Potential adverse effects of phytoestrogens. J Nutr 125:771S-776S
Whitten, P L; Lewis, C; Russell, E et al. (1995) Phytoestrogen influences on the development of behavior and gonadotropin function. Proc Soc Exp Biol Med 208:82-6
Whitten, P L; Russell, E; Naftolin, F (1994) Influence of phytoestrogen diets on estradiol action in the rat uterus. Steroids 59:443-9
Whitten, P L; Lewis, C; Naftolin, F (1993) A phytoestrogen diet induces the premature anovulatory syndrome in lactationally exposed female rats. Biol Reprod 49:1117-21
Whitten, P L; Naftolin, F (1992) Effects of a phytoestrogen diet on estrogen-dependent reproductive processes in immature female rats. Steroids 57:56-61
Whitten, P L; Russell, E; Naftolin, F (1992) Effects of a normal, human-concentration, phytoestrogen diet on rat uterine growth. Steroids 57:98-106