Effects of neonatal treatment with phytoestrogens, genistein and daidzein, on sex difference in female rat brain function: estrous cycle and lordosis

It is well known that neonatal exposure to estrogen induces masculinization or defeminization of the brain. In this study, the effects of neonatal treatment with two kinds of soybean isoflavone aglycone, genistein (GS) and daidzein (DZ), on the estrous cycle and lordosis behavior were investigated. Female rats were injected subcutaneously with 1 mg GS, 1 mg DZ, 100 microg estradiol (E2), or oil daily for 5 days from birth. As a result, vaginal opening was advanced in GS- or E2-treated females. A vaginal smear check indicated that oil- or DZ-treated females showed a constant 4- or 5-day estrous cycle, whereas GS- or E2-treated rats showed a persistent or prolonged estrus. Ovariectomy was performed in all females at 60 days of age. The ovaries in the GS- or E2-treated groups were smaller than those in the oil- and DZ-treated groups and contained no corpora lutea. In the DZ group, although corpora lutea were seen, ovaries were smaller than that of control females. Behavioral tests were carried out after implantation of E2-tubes. All of the oil- or DZ-treated females showed lordosis with a high lordosis quotient (LQ). On the other hand, as male rats, LQs were extremely low in the E2-treated group, when compared to the oil-treated group. In the GS-treated group, the mean LQ was lower than that in the oil-treated group, but higher than those in the E2-treated female or male groups. These results suggest that genistein acts as an estrogen in the sexual differentiation of the brain and causes defeminization of the brain in regulating lordosis and the estrous cycle in rats. In addition, neonatal daidzein also has some influence on ovarian function.     

Background matters: the effects of estrogen receptor alpha gene disruption on male sexual behavior are modified by background strain

One approach to study interactions between behavior and genetics is to use inbred mice with different genetic backgrounds. To examine the effect of background on a specific gene, we conducted a series of experiments with a well-characterized knockout (KO) mouse, the estrogen receptor alpha KO (ERalphaKO). The ERalphaKO mouse has so far been examined in one inbred line, C57BL/6J. Here, we examined the behavior of ERalphaKO mice within three different backgrounds mixed with C57BL/6J; DBA/2J, BALB/c, and A/J. First, we assessed masculine sexual behavior in both intact male and testosterone-treated female offspring. More ERalphaKO males in the DBA/2J (5/12) and BALB/c (5/13) backcrosses displayed intromissions and many ejaculated as compared with males in a C57BL/6J and A/J mixed background. Many fewer ERalphaKO females than males displayed masculine sexual behavior in any of the three hybrid crosses. We assessed fertility in males from the C57BL/6J by DBA/2J cross and found that one of 12 ERalphaKO males sired a litter. Several other characteristics of sexual behavior and physiology were unaffected by genetic background in ERalphaKO mice. Our data suggest that genetic background has dramatic effects on male sexual behavior and its dependence on the ERalpha gene.     

Energetic challenges unmask the role of ovarian hormones in orchestrating ingestive and sex behaviors

Effects of ovarian hormones on sex and ingestive behavior are well studied, and yet, their role in diverting attention from food to sex has not been examined directly, possibly because these functions are masked under conditions of excessive food abundance typical of the laboratory. Female Syrian hamsters were either fed ad libitum or food-restricted to 75% of their ad libitum intake for 8 days and then tested every day of the estrous cycle for their preference for males versus food, food hoarding and food intake in an apparatus designed to mimic aspects of their natural habitat. The food-restricted, but not the fed females, varied significantly over the estrous cycle in appetitive behaviors, which included their preference for males versus food and in the amount of food hoarded, with low food hoarding and high male preference on the night of ovulation. In contrast, there were no significant differences between restricted and ad libitum-fed females in the consummatory behaviors, namely, food intake or lordosis duration. In ovariectomized females, estradiol plus progesterone treatment delayed food restriction-stimulated hoarding and hastened feeding-inhibited hoarding without affecting food intake or lordosis duration. In summary, energy restriction and the presence of males unmasked an effect that was obscured in the normal laboratory conditions characterized by isolation and an over abundance of readily available food. These results are consistent with the idea that ovarian hormones orchestrate appetites for food and sex to optimize reproductive success under fluctuating energetic conditions.     

Rapid inhibition of female sexual behavior by gonadotropin-inhibitory hormone (GnIH)

Gonadotropin-releasing hormone (GnRH) is largely responsible for the initiation of sexual behaviors; one form of GnRH activates a physiological cascade causing gonadal growth and gonadal steroid feedback to the brain, and another form is thought to act as a neurotransmitter to enhance sexual receptivity. In contrast to GnRH, gonadotropin-inhibitory hormone (GnIH) inhibits gonadotropin release. The distribution of GnIH in the avian brain suggests that it has not only hypophysiotropic actions but also unknown behavioral actions. GnIH fibers are present in the median eminence (ME) and are in apparent contact with chicken GnRH (cGnRH)-I and -II neurons and fibers. In birds, cGnRH-I regulates pituitary gonadotropin release, whereas cGnRH-II enhances copulation solicitation in estradiol-primed females exposed to male song. In the present study, we determined the effects of GnIH administered centrally to female white-crowned sparrows. A physiological dose of GnIH reduced circulating LH and inhibited copulation solicitation, without affecting locomotor activity. Using rhodaminated GnIH, putative GnIH binding sites were seen in the ME close to GnRH-I fiber terminals and in the midbrain on or close to GnRH-II neurons. These data demonstrate direct effects of GnIH upon reproductive physiology and behavior, possibly via separate actions on two forms of GnRH.     

Contributions of estrogen receptor-α and estrogen receptor-β to the regulation of behavior

Studies of the mechanisms by which estrogens influence brain function and behavior have advanced from the explication of individual hormone receptors, neural circuitry and individual gene expression. Now, we can report patterns of estrogen receptor subtype contributions to patterns of behavior. Moreover, new work demonstrates important contributions of nuclear receptor coactivator expression in the central nervous system. In this paper, our current state of knowledge is reviewed.     

The nitric oxide pathway participates in estrous behavior induced by progesterone and some of its ring A-reduced metabolites

Intracerebral and intravenous administration of progesterone (P) and its ring A-reduced metabolites induces intense sexual behavior (lordosis and proceptivity) in estrogen-primed rats. The present study tested the hypothesis that the nitric oxide-cGMP-protein kinase G pathway is involved in the facilitation of sexual behavior induced by the intracerebroventricular (i.c.v.) administration of P (130 ng) and its ring A-reduced metabolites 5alpha-dihydroprogesterone (5alpha-DHP; 13 ng) and 5alpha,3alpha-pregnanolone (5alpha,3alpha-Pgl; 13 ng). In Experiment 1, we tested the relevance of the nitric oxide/cGMP pathway by infusing a nitric oxide synthase inhibitor or a nitric oxide-dependent, soluble guanylyl cyclase inhibitor icv before progestin administration. The lordosis induced by P, 5alpha-DHP and 5alpha,3alpha-Pgl was significantly reduced at 2 h after progestin infusion by the previous injection of either a nitric oxide synthase inhibitor or by a soluble guanylyl cyclase inhibitor. Lordosis behavior returned to control values by 4 h. In Experiment 2, i.c.v. infusion of the protein kinase G inhibitor KT5823 significantly inhibited the lordosis behavior induced by all three progestins at 2 h. These data support the hypothesis that the nitric oxide/cGMP/protein kinase G pathway is involved in the lordosis induced by P and some of its ring A-reduced metabolites.     

Estrogenic effects of zearalenone on the expression of progestin receptors and sexual behavior in female rats

Zearalenone is a resorcylic acid lactone compound that is produced by fungal infection of edible grains and is believed to influence reproduction by binding to estrogen receptors. In order to study the potential estrogenic effects of this compound in the brain, we examined the effects of zearalenone on the expression of neuronal progestin receptors and feminine sexual behavior in female rats. Ovariectomized rats were treated with zearalenone (0.2, 1.0, or 2.0 mg), estradiol benzoate, or vehicle daily for 3 days. They were then either perfused, and progestin receptors visualized by immunocytochemistry, or injected with progesterone and tested for sexual receptivity with male rats. Progestin receptor-containing cells were counted in the medial preoptic area and ventromedial hypothalamus. The two highest doses of zearalenone increased the concentration of neuronal progestin receptors, as did 10 microg of estradiol. The highest dose of zearalenone (2 mg) also induced progestin receptor staining density comparable to that of 10 microg of estradiol benzoate. In behavioral tests, ovariectomized animals treated with 2 mg of zearalenone followed by progesterone showed levels of sexual receptivity comparable to females treated daily with estradiol benzoate (2 microg) followed by progesterone. These studies suggest that, although structurally distinct and less potent than estradiol, zearalenone can act as an estrogen agonist in the rat brain.     

A daily rhythm in mating behavior in a diurnal murid rodent Arvicanthis niloticus

The time of day at which mating occurs is dramatically different in diurnal compared to nocturnal rodents. We used a diurnal murid rodent, Arvicanthis niloticus, to determine if inverted rhythms in responsiveness to hormones contribute to this difference. Male and hormone-primed female grass rats were tested for mating behavior at four different times of day (ZT 5, 11, 17, 23; ZT 0=lights-on). In females, there was considerable inter-individual variability with respect to patterns of responsiveness to hormones. Overall, the lordosis quotient (LQ) was rhythmic with a single peak just before lights-on (ZT 23); however, while roughly half of the females (7/15) exhibited this clear daily rhythm, the remaining animals (8/15) had relatively high LQs that did not change as a function of time. Males had their shortest ejaculation latencies and their highest number of ejaculations at ZT 23. Rhythms in mount frequency and post-ejaculatory refractory period were bimodal, with peaks around lights-on and -off (ZT 23 and 11). This temporal pattern of mounting behavior closely parallels previously documented patterns of general activity, whereas rhythms in the more reflexive components of sex behavior (LQ and ejaculation) had more restricted peaks that coincided with just the onset of rhythms in general activity. These rhythms in sexual behavior are essentially reversed relative to those previously documented in lab rats.