Hormonal control of receptivity,proceptivity and sexual motivation

The results of three experiments using ovariectomized female rats are reported. In each experiment, females were individually tested in large arena with a partner (or partners) tethered so as to give the unrestrained female control over the occurrence of social interaction. In the first experiment we show that ovariectomized females will repeatedly approach a sexually active male and allow themselves to be mounted. Other forms of female initiated contact are common. These include “grooming” and “nosing” the male, crawling over or under the male, the “push-past” the male, genital sniffing, and following the male. For convenience we refer to these as feminine social contacts. Treatment with ovarian hormones induces sexual receptivity, increases the frequency with which females approach males, and increases the display of sexual soliciting behaviors such as hopping and darting. In this setting the frequency of feminine social contacts is decreased. In a second experiment we show that hopping/darting is frequently displayed by intensely receptive females when they are tested with sexually active males, but these beahviors are almost never displayed in the presence of either a sexually passive male or a female. The frequency of feminine social contacts varies predictably with the setting: contact frequency is low when receptive females are tested with active males; contact frequency is high when females are tested with a passive male or a female. In the third experiment we used a preference test paradigm to measure sexual motivation. This involved testing a female with a sexually active male and a sexually inactive castrate at the same time. Treatment with ovarian hormones increases a female's preference for the sexually active male over the castrate, and by this criterion hormonal stimulation can be said to increase sexual motivation. The results of this experiment, using a very simple test for sexual motivation, form the basis for a forthcoming series of papers dealing with the effects of brain damage upon reflexive and volitional components of feminine sexual behavior.     

Zaprinast, a phosphodiesterase type-5 inhibitor, alters paced mating behavior in female rats

Nitric oxide (NO) is the primary mediator of blood flow in female genital tissues and drugs that enhance the activity of nitric oxide, such as phosphodiesterase type-5 (PDE-5) inhibitors, increase vaginal blood flow in anesthetized rats. The goal of the present study was to test the effects of one PDE-5 inhibitor, zaprinast, on the display of sexual behaviors in gonadectomized, estrogen- and progesterone-treated female rats. Experiment 1 demonstrates that zaprinast alters paced mating behavior by lengthening the contact-return latency to ejaculation; there is a significant relationship between dose of zaprinast (range 1.5-6 mg/kg) and contact-return latency to ejaculation. Experiment 2 illustrates that zaprinast has no effect on preference for an intact male as measured in a No Contact partner preference test. Rats receiving zaprinast tend to exhibit reduced locomotor activity in both experiments. Collectively, these findings demonstrate that modulation of the NO-cGMP pathway using a PDE-5 inhibitor alters the display of paced mating behaviors in rats.     

Neonatal decortication and adult female sexual behavior

Neonatal lesions of the cerebral cortex in female rats did not eliminate female sexual behavior as measured by lordosis. However, lordosis in response to prolonged low levels of estradiol benzoate (1.0 μg/day for 6 days) was attenuated in lesioned females. Following estradiol benzoate plus progesterone (0.5 mg) treatment the probability of lordosis increased markedly in the decorticate females, but still remained below control levels. Decorticate females were mounted by the male at least as often as control females. Hopping and darting and rejection behaviors on the part of the female were virtually eliminated in the decorticate group. However, these females continued to direct sniffing behavior toward the male at levels above those of the controls.     

Midbrain lesions eliminate sexual receptivity but spare sexual motivation in female rats

To measure sexual motivation we have used a preference test paradigm which involves testing a female with a sexually active male and a sexually inactive castrate male at the same time. On the assumption that a sexually motivated female will choose to spend more time with a partner who can provide her with stimulation appropriate to her motivational state, a female can be said to be sexually motivated to the extent that she spends more time with the active male than with the castrate. We find that bilateral destruction of the midbrain peripeduncular region eliminates the lordosis reflex in female rats, and abolishes sexual soliciting darting responses. Lesioned females treated with ovarian hormones continue, however, to show a strong preference for a sexually active male over a castrate. Thus, although peripeduncular destruction eliminates copulatory behavior, such destruction appears to spare hormone dependent systems for sexual motivation.     

Estradiol plus progesterone treatment and precopulatory behavior in ovariectomized female rats

The effects of progesterone in ovariectomized female Wistar rats, chronically injected with estradiol plus progesterone, were determined utilizing a scale of sexual responsiveness (SR) based on the hierarchical organization of copulatory (lordosis posture) and precopulatory (presenting posture, hopping, darting) behaviors. Standardized mating tests were performed 48 hours after estradiol dipropionate application (E) and 4 hours after progesterone (P) application. Experiment 1: Starting with the 5th day following ovariectomy animals in two groups were injected SC with 15 μg E in regular weekly intervals (for 8 weeks), the animals in one of the groups obtaining further SC injections of 1.0 mg P 44 hours later. The SR intensity induced by E and P application gradually increased and was eventually higher than in the E application. Experiment 2: Animals primed with 6 μg E were divided into four groups that received different P doses: 0.0, 0.4, 1.0 or 2.2 mg. This treatment lasted 11 weeks. Increased SR occurred only with the 1.0 and 2.2 mg P doses. However, these doses were equally effective. Experiment 3: Animals in five groups obtained 3, 5, 10, 15 or 30 μg E for 7 weeks. Every female was also given weekly injections of P that ranged from 0.0 to 2.4 mg. With 3, 5 and 10 μg E there were only small differences in the SR induced by small and large doses of P. On the other hand, animals receiving 15 μg E were differentially affected by P injections. Higher injected doses of P increased the SR induced by 15 μg E. The 30μg E dose combined with injections of P around 0.6 mg induced higher SR than when combined with injections of P over 1.0 mg. Experiment 4: Animals utilized in Experiment 3 which had received 30 μg E were subjected to further experimentation. The deletion of P caused a rapid decrease in SR. A predicted increase in SR was observed after reintroducing the 0.6 mg P administration. Finally, after the E and P administrations were stopped, precopulatory behavior disappeared but the females still exhibited the lordosis posture two weeks later. Based on these results the general conclusion is made that the dose-response relationship between progesterone and proceptive (precopulatory) behavior is dependent on the quantity of estradiol which is jointly administered. By certain combinations of dosage levels of estradiol and progesterone, the highest level of sexual responsiveness can be induced in ovariectomized rats.     

Female sexual behavior in male rats: effect of hour of castration at birth

In the male rat, a dramatic increase in serum testosterone occurs during the first four hours of postnatal life. The experiments sought to determine whether such an increase would participate directly on the defeminization process. Newborn male rats were castrated either at 0 hr in utero (literally at the moment of birth) or at 6 or 12 hrs after birth. Some males were castrated at 0 hr in utero and injected at the time of surgery with 1 or 5 micrograms testosterone propionate (TP). At about 90 days of age, each animal was injected with estrogen and progesterone and tested for female sex behavior. Males castrated at 0 hr in utero displayed typical female sex behavior. Males castrated at 6 or 12 hrs after birth were less receptive than males castrated at 0 hr. Males castrated at 0 hr and injected with testosterone at this time almost never showed lordosis as adults after treatment with ovarian hormones. These results are consistent with the idea that the rapid elevation in serum testosterone which occurs shortly after birth suppresses the development of sexual behavior sensitivity to ovarian hormonal stimulation.     

The effects of sexual experience and estrus on male-seeking motivated behavior in the female rat

Ovariectomized (OVX) female rats were trained to traverse a straight alley and return to a goal box where they had previously encountered a male rat, a female rat or an empty goal box. The time required to run the alley was used as an index of the subjects' motivation to re-engage the goal box target. Subjects were tested in both estrus and non-estrus, first sexually naïve and then again after sexual experience. Female rats ran most quickly for a male target, most slowly for an empty goal box, and at intermediate speeds for a female target. Sexual experience tended to slow run times for all but male targets. Estrus enhanced approach behavior for males and an empty goal box, but tended to slow the approach toward females, both before and after sexual experience. This latter finding was further investigated in a second experiment in which sexually naïve OVX females were tested during estrus and non-estrus in a locomotor activity apparatus, a runway with an empty goal box, and an open field. Estrus produced no changes in spontaneous locomotion either in the activity box or the open field, but decreased run times in the alley and increased the number of center-square entries in the open-field. Thus, estrus produces increases in sexual motivation that selectively enhance exploratory, presumably male-seeking behavior, but not simple spontaneous locomotion.     

Effects of progesterone on lordotic responses to specific mating stimuli in hamsters

Mating-induced inhibition of sexual receptivity was examined in ovariectomized, estrogen (E) treated and estrogen plus progesterone (E + P) treated hamsters given 10 min of exposure to male mounting stimulation alone or to mounts, intromissions, and ejaculations at eight hourly intervals. In E + P treated females, no differential effects of exposure to full mating stimulation vs. mounting stimulation alone were observed. In contrast, females given E treatment alone showed a marked differential response. Fully mated, E-treated females showed more lordosis than E-treated females exposed to mounts alone during the initial test. However, total lordosis duration declined precipitiously in the fully mated group by 2 hr and remained significantly below that in other groups during subsequent tests. Levels of receptivity in E-treated females mounted-only remained relatively constant until 8 hr. These results suggest that P reduces the inhibitory effects of vaginocervical cues received during mating without affecting the response to mounting stimulation alone. In addition, vaginocervical stimulation may initially facilitate lordosis in E-treated females.     

Influence of female copulatory behavior on the induction of pseudopregnancy in the female rat.

Female regulation of inter-intromission intervals and the successful induction of pseudopregnancy were investigated. Three groups of intact female rats received 5, 10 or 15 intromissions, respectively, in a two-compartment escape-re-entry mating arena in the presence of three sexually vigorous males. Three additional groups of intact females received 5, 10 or 15 intromissions in the same arena but were not allowed access to the escape platform and thus were not allowed to pace their sexual contacts. Five intromissions were sufficient to induce pseudopregnancy in a majority of females allowed to pace their sexual contacts, as compared with females in the no-escape condition. With increasing numbers of intromissions (10 and 15 intromissions) pseudopregnancy was seen in a majority of females in both the escape and no-escape conditions. Inter-intromission intervals were extended for all escape groups. The results demonstrate that female regulation of the temporal receipt of intromissions contributes a complementary behavioral component to the mating sequence which can potentiate the stimulation of intromissions by the male.     

The display of paced mating behavior in a rat model of endometriosis

Endometriosis is a disorder associated with chronic pelvic pain and ill effects on women's sexual health. The present study examined the effects of pelvic endometriotic implants on the display of paced mating behavior in female rats. Approximately 2 months after the surgical induction of endometriosis, rats were tested for paced mating behavior during proestrus (Experiment 1) or after bilateral ovariectomy and hormone replacement (Experiment 2). Although endometriotic implants were confirmed at autopsy, rats with surgical endometriosis in both experiments exhibited normal patterns of paced mating behavior. The positive relationship between implant material and contact-return latency following ejaculation in Experiment 2 suggests that the sensitivity to vigorous mating stimulation may be influenced by endometriosis.     

Neonatal gonadal hormones: Effect on maternal and sexual behavior in the female rat

It has been found that significant differences exist between male and female rats of the Long-Evans strain on maternal behavior when the animals were presented with rat pups for seven consecutive days. The presence of ovarian or testicular products at the time of maternal testing did not have a facilitating or suppressing effect on maternal behavior in the Long-Evans rat. Females given 100 μg or 1 mg of testosterone propionate (TP) four days after birth and gonadectomized at 25 days of age behaved like control females (oil injected four days after birth and gonadectomized at 25 days of age) on measures of maternal behavior, but showed significantly lower sexual receptivity when primed with estrogen and progesterone. Thus the female sexual behavior system was suppressed by neonatal TP, but the maternal mediating system was not suppressed by the same treatment. It is concluded that the critical periods of differentiation may be different for sex and maternal behavior.     

Sexual receptivity: Brain sites of estrogen action in female hamsters

In order to investigate the brain sites of estrogen action, ovariectomized hamsters were stereotaxically implanted with unilateral 27 gauge cannulae containing estradiol. Groups of females received implants into either the lateral septum, bed nucleus of the stria terminalis, preoptic area, anterior hypothalamus, ventromedial hypothalamus, arcuate nucleus, corticomedial amygdala or mesencephalic central gray. Another set of animals received implants containing cholesterol. One week later the animals were injected with progesterone and 4–5 hours later tested for sexual receptivity. The most receptivity and the most consistent response was seen in females with estradiol implants in the ventromedial hypothalamus. Only a few scattered animals in the other anatomical groups showed any receptivity. Only in animals with implants in the anterior hypothalamus was there any evidence of leakage of estrogen into peripheral circulation as measured by uterine weight. There was no response in females with cholesterol implants. Our results suggest that the ventromedial hypothalamus is the most sensitive brain area for the estrogenic induction of female sexual receptivity in hamsters.     

Theoretical review. Progesterone: inhibition of rodent sexual behavior.

The inhibitory effects of progesterone (P) can be observed in many vertebrates of either sex. In female rodents, P man act to terminate the period of receptivity and to prevent proestrus reinduction of receptivity at times when plasma P is minimal (immediately postestrus) or maximal (during the luteal phase). Inhibition is probably accomplished via an interaction with estrogen although P does have profound general anesthetic properties. Inhibition of receptive behavior has been induced by P implanted in the rodent midbrain, but implants in other regions of the central nervous system were ineffective. This correlates with the observation that rodent midbrain concentrates P more that other brain regions. Modes of progesterone-estrogen interaction are discussed.     

Progesterone-induced mating behavior in rats on the day following spontaneous heat

Three experiments were designed to test the ability of exogenous progesterone administered shortly after the termination of spontaneous heat to induce a second period of sexual receptivity. In female rats displaying four-day estrous cycles, a second period of sexual receptivity could be induced by exogenous progesterone administered before, but not after, 1100 hrs on the day following spontaneous heat. In a second experiment, animals given coital stimulation on the evening of proestrus were found to exhibit a second period of progesterone-induced receptivity equal in intensity to that of animals not receiving such stimulation. In the final experiment, various amounts of progesterone were administered to ascertain the relationship of dose and response. Dosages of 2.5 mg, 1.5 mg and 1.0 mg were equally effective in inducing mating behavior while a linear decrease was observed with smaller amounts. These results indicate that the neural substrate responsible for lordosis behavior is capable of reacting with progesterone administered early on the morning of the day following spontaneous heat to produce a second period of sexual receptivity.     

Estradiol treatment and precopulatory behavior in ovariectomized female rats

Female rats of Wistar strain were injected SC, starting at Day 5 after ovariectomy, with estradiol dipropionate (ED) at weekly intervals. Forty-eight hours after each injection they were subjected to standardized mating tests. A 6 μg ED dose showed to be insufficient to maintain estrous behavior. Both precopulatory and lordosis behavior disappeared in the course of eight weeks. On the other hand, the behavioral effectiveness of 10 and 30 μg ED increased with the number of injected doses. Under these circumstances, estradiol proved to be sufficient to induce not only full copulatory readiness but also all the degree of precopulatory behavior of pattern (Presenting, Hopping ending in Presenting, and Darting ending in Presenting). Although there are large individual differences in behavioral effectiveness of ED, the estradiol thresholds for inducing Presenting, Hopping, and Darting were found to increase in the given order. However, prolonged (up to Week 12) treatment with 30 μg ED resulted in the disappearance all estrous behaviors. This decline of estradiol effectiveness was reversed by increasing the estradiol dose to 100 μg.     

Age differences in copulatory behavior and serum 17β-estradiol in female rhesus monkeys

Young, sexually mature female rhesus monkeys housed in outdoor groups have been found to exhibit significantly longer mating periods associated with first conception compared with the duration of the annual mating period exhibited by older, multiparous females. An analysis of the sexual behavior and corresponding serum concentrations of 17β-estradiol (E2) and progesterone (P) in two age groups of rhesus females revealed that young females copulated on significantly more days prior to the E2, ovulatory peak than did older females. Serum concentrations of E2 were significantly higher from ?30 to Day ?10 prior to the E2 peak (Day 0) in young females. Estradiol concentrations were similar for both age groups during the remaining follicular and periovulatory period. No age differences in serum P were observed between the two groups. Serum E2 levels associated with the onset of mating were similar in the two age groups with levels rising from 73.5±4.0 pg/ml prior to mating to 97.2±4.6 pg/ml. Thus the hormonal profile associated with the onset of mating is similar for both age groups, and the earlier occurrence of mating behavior prior to ovulation in young females is accounted for by an earlier rise in serum E2.     

Ventromedial hypothalamic damage and sexual proceptivity in female rats

Sexual proceptivity is indicated by behaviors which reflect feminine initiation with respect to the occurrence of mating behavior. In this study we used ovariectomized female rats, and tested for sexual behavior in a relatively large arena with a sexually active male tethered in one corner. This testing situation gave the unrestrained female control over the occurrence of sexual interaction, and the frequency with which a female approaches a sexually active male provides a measure of sexual proceptivity. We find that administration of estrogen and progesterone to neurologically intact female rats induces sexual receptivity and increases the frequency with which they approach a sexually active male. Bilateral destruction of the ventromedial hypothalamus renders females non-receptive and virtually eliminates the tendency for females to approach males. Bilateral sagittal knife cuts which bracket the ventromedial region produce similar effects. Apparently, the ventromedial hypothalamus is importantly involved in the control of both receptive and proceptive components of feminine sexual behavior.     

The role of reinforcement in the sexual behavior of the female rat

In order to clarify the role of reinforcement in the sexual behavior of female rats, females were trained to traverse a runway to achieve contact with incentive males. Females learned to run faster to sexually active males that achieved intromission than to passive males (p<0.05). However, both types of incentive males produced significant learning (p< 0.001). The type of estrus, either natural or hormone-induced, did not affect learning measures. The results were interpreted as requiring that an explanatory model of the female's sexual behavior contain a variable accounting for reinforcement specific to sexual contact as well as for the more general social reinforcement and the well established aversive consequences of mating.     

Testosterone aromatization in high and low mating lines of gallinaceous birds

Capons from high (HML) and low (LML) mating lines of Japanese quail and chickens received testosterone propionate, 5α-dihydrotestosterone (5α-DHT) or estradiol benzoate injections after which copulatory behavior was observed during exposure to live females and to a female model. With live females, the testosterone-treated HML capons mated significantly more than the other HML groups. All LML capons mated infrequently and at comparable levels. When tested with the model, estrogen-treated LML capons mated significantly more frequently than testosterone-treated LML capons, suggesting testosterone aromatization rate was affecting mating activity. This possibility was tested with HLM and LML intact cocks and capons receiving silastic implants of either testosterone, 5α-DHT or a combination of estradiol and 5α-DHT (E+DHT). Mating activity of intact HML cocks, T-treated, and E+DHT-treated HML capons were similar, and all groups mated significantly more than the control or 5α-DHT-treated capons. There were no significant differences between any of the LML groups. The data suggested that limited testosterone aromatization was not the cause of relatively reduced sexual activity in the LML males.     

Involvement of the ventromedial and anterior hypothalamic nuclei in the hormonal induction of receptivity in the female rat

Bilateral lesions of the ventromedial hypothalamic area virtually eliminated the estrogen-induced display of sexual receptiveness in the female rat. Such lesions usually diminished sexual responsiveness to combined estrogen-progresterone stimulation, although not all lesions were equally effective in this regard. Damage to the anterior hypothalamic area was without apparent effect on the hormonally-induced display of receptivity, suggesting that previous observations to this effect are probably related to incicental damage to the ventromedial hypothalamic area incurred during placement of the lesions. This study complements other work indicating that the ventromedial hypothalamic area is relatively rich in estradiol concentrating cells and that estrogen implants to this area induce sexual receptivity in spayed female rats. Together, these studies affirm that the ventromedial hypothalamic area plays a critical role in the hormonal induction of receptivity in female rats.