A contributory role for midbrain progesterone in the facilitation of female sexual behavior in rats

Progesterone (P) facilitation of sexual receptivity in rodents has been achieved by intracranial administration to the ventral hypothalamus; the preoptic area; and midbrain areas such as central gray, mesencephalic reticular formation, and ventral tegmental nucleus. In our laboratory, by far the most effective site in rats has been the ventromedial nucleus of the hypothalamus (VMN). However, several reports of sensitivity to P in the midbrain of rats and other rodent species led us to investigate whether stimulation of the ventral midbrain of female rats might contribute to facilitation of sexual receptivity. Ovariectomized Long-Evans rats received one cannula aimed at the VMN, and another aimed at the contralateral ventral mesencephalon. P in both cannulae, following a priming dose of estradiol, caused significantly higher lordosis quotients (LQ) than blank tubes. Controls with bilateral cannulae in the VMN responded when both tubes were filled with P, but did not respond to unilateral VMN P stimulation. P in the VMN and contralateral anterior preoptic area did not result in a greater degree of receptivity than did the empty tubes. These studies indicate that although progesterone stimulation in the midbrain alone is not sufficient to facilitate receptivity in female rats with our methods, the midbrain may play an auxiliary role. P implants in the midbrain appear to facilitate receptivity in the case of VMN implant treatments that are subthreshold for stimulating lordosis. The results are discussed in light of similar studies in other rodent species, and in the context that more than one brain site may be important in the natural stimulation of sexual receptivity by gonadal hormones.     

A soy supplement and tamoxifen inhibit sexual behavior in female rats

In addition to displaying proceptive (hopping and darting) and receptive (lordosis) behaviors during a sexual encounter with a male, female rodents will regulate the timing of the encounter by engaging in a series of approaches and withdrawals from the male, a behavior termed paced mating behavior. Proceptive, receptive, and paced mating behaviors are all regulated by, and sensitive to, estrogen and progesterone, suggesting that compounds capable of disrupting these critical hormones may also perturb the display of female sexual behavior. The present experiments examined the impact of the selective estrogen receptor modulator (SERM) tamoxifen and a popular soy phytoestrogen dietary supplement on female sexual behavior in rats. Ovariectomized female rats were given either tamoxifen (TAMOX) by implant or the soy supplement through the diet then injected with estradiol benzoate (EB, 10 microg) or oil followed 48 h later with an injection of progesterone (P, 500 microg). Animals were then tested for sexual behavior 4 h after the P injection. Neither compound had any effect on sexual behavior when administered in conjunction with P alone; however, both significantly diminished receptive behavior, as measured by the lordosis quotient (LQ), in animals primed with both EB and P. Similarly, the hopping and darting rate was also significantly depressed in both the soy- and TAMOX-treated animals, compared to the EB- and P-treated controls, with the soy-treated animals showing significantly less proceptive behavior than the TAMOX-treated animals. Finally, soy but not TAMOX significantly attenuated paced mating behavior in animals compared to the EB- and P-treated controls. These results demonstrate that both the soy supplement and TAMOX act as estrogen antagonists on both proceptive and receptive behavior in female rats.     

Decline of sexual behavior in castrated male rats: Effects of female precopulatory behavior

From the population of 89 adult sexually inexperienced Wistar male rats 20 animals that initiated copulatory behavior with females exhibiting low intensity of precopulatory behavior (presenting females) were preselected. Prior to castration all 20 males had the same sexual experience: three ejaculatory series in four weekly sessions with females exhibiting high intensity of precopulatory behavior (darting females). Following castration, the decline of copulatory behavior was much slower for the nine males tested with darting females as compared to the 11 males tested with presenting females. Male precopulatory behaviors (anogenital sniffing, touching flanks, etc) outlasted the loss of copulatory behavior and seem to be less dependent on both external and internal determinants. It is concluded that intensive external sexual stimuli can function to compensate, and therefore mask, the subnormal operation of androgen-dependent mechanisms in initiating the copulatory behavior.     

Medroxyprogesterone acetate acutely facilitates and sequentially inhibits sexual behavior in female rats

Medroxyprogesterone acetate (MPA), a synthetic progestin commonly used in contraception and hormone replacement therapy, appears to inhibit libido in women, but little is known about the mechanisms through which it may exert this effect. We compared the acute and sequential actions of MPA and natural progesterone (P4) on sexual behavior in female rats to test the hypothesis that MPA inhibits sexual behavior, at least in part, by acting as a potent progesterone receptor (PR) agonist. Ovariectomized females were placed in one of three dose groups (high, mid, or low), and each subject was tested under three different conditions (MPA, P4, and vehicle). The order of progestin treatment was balanced among subjects, and within each dose group equimolar quantities of MPA and P4 were administered. During each trial, females were injected with estradiol benzoate (EB, 4 mug) followed by one of three progestin treatments (MPA, P4, or vehicle) at +44 h, and behavioral testing at +48 h. On the next day, all females were given a standard 500-microg injection of P4 at +68 h and were tested again for sexual behavior at +72 h. On the first day of behavioral testing, both MPA and P4 induced a pronounced rise in receptive and proceptive behavior at the mid and high doses, but at the lowest dose MPA had a much greater effect in comparison to P4. On the second day of behavioral testing, MPA attenuated the expression of proceptive and receptive behavior at both the mid and high doses, whereas P4 only attenuated the expression of lordosis and only did so at the highest dose. These findings illustrate that MPA and P4 have a similar impact on sexual behavior in female rats and suggest that the inhibitory effects of MPA may be attributable, at least in part, to its potent effects at the progesterone receptor.     

A role for Src kinase in progestin facilitation of estrous behavior in estradiol-primed female rats

This study tested the hypothesis that the Src/Raf/MAPK signaling pathway is involved in the facilitation of the lordosis and proceptive behaviors induced by progesterone (P) and its ring A-reduced metabolites in ovariectomized, estradiol-primed rats. Intraventricular (icv) infusion of PP2 (7.5, 15 and 30 µg), a Src kinase inhibitor, significantly depressed P-dependent estrous behavior (lordosis and proceptivity) in estradiol-primed rats. Icv infusion of 30 µg of PP2 also significantly attenuated estrous behavior induced by the ring A-reduced P metabolites 5α-dihydroprogesterone (5α-DHP) and 5α-pregnan-3α-ol-20-one (allopregnanolone). PP2 did not inhibit estrous behavior induced by administration of high doses of estradiol alone to ovariectomized rats. We also assessed if the ventromedial hypothalamus (VMH) is one of the neural sites at which progestins activate Src signaling to facilitate estrous behavior. Bilateral administration of 15 µg of PP2 into the VMH inhibited the stimulation of both lordosis and proceptive behaviors elicited by subcutaneous P administration to estradiol-primed rats. These results suggest that progestins act through Src/Raf/MAPK signaling to initiate estrous behaviors in estrogen-primed rats. This event is one component of the cellular pathways leading to the display of estrous behaviors induced by P and its ring A-reduced metabolites in female rats.     

Family background and female sexual behavior

Since the seminal works of Draper and Harpending (1982) and Belsky et al. (1991) there has been considerable interest in the link between the family environment experienced as a child and consequent mating and reproductive strategy of females. In this paper, predictions from the hypothesis were tested using postal survey data from a cross-section of 415 women in Merseyside, UK. No relationships were found between father-absence, unrelated male-presence, parental divorce or parental death with age at first coitus, number of sexual partners, mean length of sexual relationships or mean length of relationships prior to coitus occurring. This work was supported by an Economic and Social Research Council Studentship. This paper was completed as part of the author’s doctoral research that focused on differences in age at first reproduction between social classes in the UK, conducted at the University of Liverpool. The author now works for the Scottish Executive, Edinburgh.     

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.     

Hormonal control of female sexual behavior in the rat

Graded amounts of estradiol benzoate (ranging from 0.48 to 500 μg/kg) were administered to ovariectomized, adrenalectomized female rats in order to analyze the effects of estrogen on the qualitative and quantitative aspects of female reproductive behavior in this species. The interaction of hormone dose and copulatory stimulation was also investigated. In this study, soliciting behavior and lordosis responses were broken down into subcategories. There were three main results. First, it was found that the responses were hierarchically arranged such that, with increasing doses of hormone, the common elements of sexual responding appeared in the same order across individual females. Second, the chronic endocrine background of the female influenced the degree of her receptivity following an acute injection of estrogen. Third, repeated elicitation of lordosis by copulatory stimulation facilitated the subsequent occurrence of lordosis.     

Studies on the possible role of 2-OH-estradiol in the control of sexual behavior in female rats

$\text{In vitro}$ studies have revealed that 2-OH-estradiol can be produced in the brain and that it can compete with estradiol for hypothalamic cytosol binding sites. In the present study ovariectomized female rats received 2-OH-estradiol via sc or iv injections and/or via direct intracerebral implantation either alone or in combination with vehicles, estradiol or testosterone. Behavioral tests after sc progesterone priming indicated that 2-OH-estradiol has relatively weak estrogenic, and no apparent anti-estrogenic or antiaromatization activity in the induction of sexual receptivity.     

Pinealectomy and sexual rhythm in female rats.

The role of the pineal gland in inducing and maintaining the persistent estrus of rats exposed to continuous illumination was examined. Under the cyclic illumination, the pinealectomy or sham-operation revealed no effect on the estrous cycle, although weights of the ovaries, adrenals and hypophysis were slightly but definitely greater in the pinealectomized animals. In rats exposed to the continous illumination immediately after pinealectomy or sham-operation, both groups exhibited the persistent estrous states soon after the change of lighting condition. In these rats, neither the degree of persistent estrus nor the organ weights a autopsy showed any significant difference between the groups. Moreover, the pinealectomy could not alter the incidence of estrous in persistent estrous rats which had been established already by the continuous illumination.     

Prenatal endogenous androgenic influences on masculine sexual behavior and genital morphology in male and female rats

Female rats located near a male during uterine development showed increased frequencies of male-like behavior as adults and virilization of genital morphology. These changes in behavior and morphology were blocked by prenatal treatment with the anti-androgen, Flutamide.     

Long-term ovariectomy and hormone-induced sexual behavior, progestin receptors, and hypothalamic morphology in female rats

Long-term ovariectomy reduces the ability of estradiol and progesterone treatment to induce sexual receptivity in female rats. Previous researchers suggested that this effect may be due to a decreased induction of neural progestin receptors by estradiol in the long-term ovariectomized rats. The present study was designed to replicate and extend this finding, and to search for neuroanatomical correlates by measuring the volume of the ventromedial nucleus (VMN) of the hypothalamus, a putative site of action of estradiol and progesterone for the induction of female sexual behavior. Long-term ovariectomy (5 to 6 weeks) as compared to short-term ovariectomy (1 week) reduced the ability of estradiol-17 beta and progesterone treatment to induce sexually receptive and proceptive behaviors. Consistent with previous reports, our data show that the reduced levels of cytosol progestin receptors after long-term ovariectomy and estradiol treatment are related to a reduced ability of estradiol to induce the receptors. Long-term ovariectomy did not affect the concentration of cytosol progestin receptors in the preoptic area, suggesting a neuroanatomical specificity to this effect. Contrary to our predictions, long-term ovariectomy did not affect the volume of the VMN. In fact, estradiol treatment, while blocking the effect of long-term ovariectomy on sexual behavior, decreased the volume of the VMN. Therefore, the measurement of the volume of the VMN is not a good predictor of the responsiveness to steroid hormone induction of sexual behavior.     

Inhibition of estrogen facilitation of sexual behavior by the intracerebral infusion of actinomycin-D

It has been shown previously that intracerebral actinomycin-D (Act-D) pellets inhibit estrogen facilitated female sexual behavior, but it was not possible to test the reversibility of this effect. In the present study an attempt was made to distinguish between the possible temporary interruption by Act-D of the biochemical action of estrogen which facilitates sexual receptivity and permanent toxic effects of the drug. Act-D in saline was infused into the third ventricle or the preoptic area (POA) to determine whether a reversible suppression of sexual behavior as measured by the lordosis quotient (LQ) could be produced. Ovariectomized rats were implanted with midline guide tubes entering the third ventricle (eight rats) or with bilateral tubes extending to the corpus callosum above the POA (67 rats). Each animal served as its own control since pretest and Act-D and recovery tests were performed 10–14 days apart in most subjects. For each behavioral test implanted subjects were primed with 3μg estradiol benzoate (EB) and 0.5 mg progesterone (P) 48 hr later. Behavioral tests, each involving 50 mounts, were performed 4–6 hr after P. Following the pretest the animals were retested under experimental conditions. Inner cannulae were inserted into the POA through the guide tubes and 0.11 μg Act-D infused 24 or 12 hr before, simultaneously with, or 6, 12, 18, or 26 hr after EB. A recovery test was performed 10–14 days later with no intracerebral infusion. The control procedure (infusion of of saline either simultaneously with or 12 hr after EB) did not alter the LQ. Act-D infusion produced a reversible suppression of lordosis which was dependent upon the time of administration of Act-D. Intraventricular infusion of Act-D 6 hr after EB reversibly inhibited lordosis behavior and no lesions were produced. Act-D infused into the POA simultaneously with EB or 6 hr later reversibly suppressed the LQ. In the 6 hr group, for example, the LQ fell from 78.3 to 35.7, but 10–14 days later reached 74.3. Although brain lesions of varying extent were produced by Act-D, the marked but reversible suppression of lordosis behavior is consistent with the view that Act-D inhibits estrogen facilitation of lordosis behavior by means of a biochemical rather than cytotoxic action.     

Inhibitory and disinhibitory effects of psychomotor stimulants and depressants on the sexual behavior of male and female rats

Drugs of abuse comprise several pharmacological classes, including psychomotor stimulants, such as amphetamine and cocaine, and CNS depressants, such as morphine and alcohol. Few studies have examined the effects of those drugs systematically on human sexual behavior, although substantial clinical and epidemiological literatures suggest that drugs in both classes either inhibit sexual responding or can be “prosexual” in certain situations, thereby increasing the potential of risky sexual activity and the spread of sexually transmitted diseases. This paper reviews original data in rats showing that both classes of drug inhibit or disinhibit sexual behavior depending on the animal's baseline level of sexual responding, hormonal status, whether the drug is given acutely or chronically, and whether the animal has learned to inhibit sexual responding toward nonreceptive partners or in the presence of conditioned olfactory cues that predict sexual nonreward.