The effects of progestins,mineralocorticoids, glucocorticoids,and steroid solubility on the induction of sexual receptivity in rats

In the first experiment, progesterone and its 5α-reduced metabolite, 5α-dihydroprogesterone, dissolved in two different vehicles were compared for their effectiveness in facilitating lordosis behavior in ovariectomized estrogen-primed rats. When dissolved in oil vehicle, 5α-dihydroprogesterone was less effective than progesterone. However, when dissolved in Tween 80 solution, the two progestins were equally effective. In the second experiment, adrenal corticoids dissolved in Tween 80 solution were tested for their relative ability to facilitate sexual receptivity. Progesterone, desoxycorticosterone, and desoxycorticosterone acetate were equally effective in facilitating sexual receptivity. Aldosterone, corticosterone, and corticosterone acetate were no more effective than the vehicle in facilitating sexual receptivity.     

Ability of different hormones to substitute for progesterone in the induction of oestrous behaviour in oestrogen-treated overiectomized ewes

Behavioural responses to teaser males were recorded in oestrogen-treated ovariectomized ewes following 5 days pretreatment with various progestins, adrenal steroids or the oil vehicle. Hormones used were, progesterone, 5-dihydroprogesterone, corticosterone and desoxycorticosterone. No clear pattern emerged from records of soliciting behaviour, and only treatment with 5-dihydroprogesterone or desoxycorticosterone produced significantly greater receptivity quotients than injection of the oil vehicle. These results indicate that further studies with progesterone metabolites could increase understanding of the mechanisms controlling reproductive behaviour in the ewe.     

Interactions of progesterone and dihydroprogesterone with dihydrotestosterone on estrogen activated sexual receptivity in female mice

Lordosis behavior in response to a mounting stimulation was quantified in ovariectomized female CD-1 and SW mice primed with estradiol benzoate and either progesterone or dihydroprogesterone. Both progestins were effective in stimulating receptivity, in CD-1 females, while only progesterone was effective in SW females. Dihydrotestosterone given concurrently with both the estrogen and progestin injections was found to have no effect on progesterone stimulated receptivity, but it produced a dose related inhibition of receptivity in the dihydroprogesterone treated females.     

Altered corticosterone status impairs steroidogenesis in the granulosa and thecal cells of Wistar rats

Hypo- and hyper-corticosteronisms have adverse effects on ovarian endocrine and exocrine functions. In the present study, the mechanism by which corticosterone in excess or insufficiency impairs steroidogenesis in granulosa and thecal cells was investigated in adult albino Wistar rats. In this regard, rats were administered with corticosterone-21-acetate (2 mg/100 g b.wt., s.c., twice daily) or metyrapone (11beta-hydroxylase blocker) (10 mg/100 g b.wt., s.c., twice daily) for 15 days and a group of corticosterone/metyrapone treated rats was withdrawn of treatment and maintained for another 15 days and killed during their diestrus phase. Administration of corticosterone-21-acetate while elevated the serum corticosterone levels, metyrapone diminished the same. Administration of metyrapone reduced the serum levels of LH and estradiol; corticosterone reduced the levels of FSH in addition to LH and estradiol. In vitro production of progesterone and estradiol by the granulosa and thecal cells was decreased due to altered corticosterone status. Whereas administration of corticosterone significantly reduced the activity of 3beta-hydroxysteroid dehydrogenases (3beta-HSD) in granulosa and thecal cells, it reduced the activity of 17beta-HSD only in granulosa cells. While metyrapone treatment reduced the activity of 17beta-HSD in granulosa as well as thecal cells, it reduced the activity of 3beta-HSD only in thecal cells. The findings of the present investigation clearly demonstrate that excess or insufficiency in corticosterone affects steroidogenic process in the ovary. This is achieved by decreasing the levels of gonadotropins probably by their diminished synthesis and secretion and by interfering at the signal transduction process of these gonadotropins.     

Effect of combined treatment with imipramine and metyrapone on the immobility time, the activity of hypothalamo-pituitary-adrenocortical axis and immunological parameters in the forced swimming test in the rat.

Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.     

Influences of exogenous epinephrine on two reproductive parameters in female mice: disruption of receptivity but not implantation.

Diverse stressors impede female receptivity and fertility. Since epinephrine is released from the adrenal during stress, it might play a role in stress-induced disruptions of female reproductive parameters. Experiment 1 examined whether exogenous epinephrine would disrupt lordosis behavior in estrogen- and progesterone-treated ovariectomized female mice. Single dosages of 20 and 40 micrograms almost eliminated sexual receptivity. Experiments 2 and 3 examined whether chronic dosages of epinephrine shortly after insemination would lead to a failure of implantation of mouse embryos. Results indicated that epinephrine had little effect on the number of dams delivering pups, the number of pups born, litter weight, or the number of stillbirths.     

Chin marking behavior, sexual receptivity, and pheromone emission in steroid-treated, ovariectomized rabbits

The effect of daily injections of estradiol benzoate (1 or 10 micrograms) and of progesterone (10 mg) on chin marking activity, sexual receptivity, and emission of nipple-search pheromone in ovariectomized rabbits was investigated. Both estradiol treatments resulted in a significant increase in all three measures over baseline and control group levels within 1-3 days, and withdrawal in a return to pretreatment levels within 2 weeks (Experiment I). In contrast, the administration of progesterone to such estradiol-primed does resulted in an almost immediate suppression of chin marking and lordosis, but in marked enhancement of pheromone emission and aggressive behavior (Experiment II). However, progesterone given alone to nonprimed does had no effect on any of these measure (Experiment III). The response profiles resulting from these treatments correspond well to patterns reported for intact does during estrus (= estradiol alone), pregnancy (= estradiol plus progesterone), and at parturition (= progesterone withdrawal).     

Inhibitory effects of ghrelin on sexual behavior: role of the peptide in the receptivity reduction induced by food restriction in mice

Ghrelin (Ghr) is a gut/hypothalamus peptide with inhibitory actions on reproductive physiology; however, there are no previous reports of its role on estrous behavior. Under the hypothesis that the increase of plasma Ghr during food restriction (FR) is responsible for receptivity reduction, we intended to evaluate the receptivity percentage of female mice subjected to: exp. 1) acute and chronic FR and Ghr administration (3?nmol/animal/day, s.?c.) and exp. 2) the co-administration of a ghrelin antagonist [ant=(d-Lys3)-GHRP-6; 6?nmol/animal/day s.?c.]. All females were ovariectomized, primed with steroids, trained, and randomly subjected every week to each one of several protocols, followed by a behavioral test. Experiment 1 (n=8): basal, no treatment; acute FR (aFR), 24-h fasting; chronic FR (cFR), 50% FR for 5 days; acute ghrelin (aGhr), Ghr 30?min before test and chronic ghrelin (cGhr), Ghr for 5 days. Except for cGhr, all treatments significantly decreased the percentage of receptivity (mean±SEM): basal 61.9±6.0, aFR 33.1±8.1, cFR 18.8±7.7, aGhr 45.6±10.6, p<0.05 vs. basal. In exp. 2 (n=11), except for cFR+ant (55.0±6.4) the co-administration of the antagonist reversed the deleterious effects detected in exp. 1: basal 70.9±5.4; aFR+ant 72.3±7.6; aGhr+ant 73.6±4.7. As expected, the administration of vehicle or antagonist alone did not modify receptivity. Besides, we found a significant correlation between percentage of body weight loss and percentage of receptivity reduction (r=0.62, p=0.0004). This is the first study demonstrating that ghrelin is able to inhibit female mice sexual behavior and that is involved, at least in part, in receptivity reduction after food scarcity.     

Natural or hormone-induced sexual and social behaviors in the female brown lemming (Lemmus trimucronatus)

The behaviors of intact or ovariectomized, estradiol benzoate-treated or estradiol benzoate followed by progesterone-treated female brown lemmings were compared. Intact, diestrous females engaged in more social interactions with a male than did ovariectomized females (Experiment 1). In the first 5 min of a 1-hr mating exposure (Experiment 2, Test A) intact females in natural estrus engaged in more social and sexual behaviors than did ovariectomized females in estrogen-induced estrus. However, during the last 5 min of the 1-hr exposure (Test B) ovariectomized females receiving estrogen alone continued to show high levels of sexual activity with a male partner, while intact estrous females or females receiving estrogen followed by progesterone showed an apparent drop in sexual receptivity and an increase in aggressivity. Aggressive behaviors, as indexed by threat-leap behaviors on the part of the female may increase in the presence of progesterone. Declines in sexual activity, occurring within 1 hr of progesterone injection, were apparently dependent on the interaction of progesterone and copulatory events which may affect both the male and female.     

Sustained influence of previous estradiol or testosterone treatments on sexual behaviors of female pigs

Two studies were conducted to determine the consequences of extended treatment with estradiol or testosterone on sexual behavior in postpubertal, female pigs. After ovariectomy, either steroid was administered for 6 weeks at dosages sufficient to maintain serum concentrations similar to those observed in mature male pigs. Behavioral evaluations were initiated 2 months after the last steroid treatment. These treatments reduced receptivity (immobile stance when placed with a mature male) and proceptivity (preference to remain near a mature male) in association with an increase in aggressive behavior. In females treated previously with both estradiol and progesterone, sexual behaviors 2 months later were similar to those of control females. When evaluations were repeated 5 months after extended estradiol treatment had ceased, receptivity and proceptivity had returned to that of control pigs and aggressive behavior had diminished greatly. Interpretation of these changes in behavior is that extended periods of estradiol or testosterone treatment sustain activational influences for a considerable amount of time after treatments cease and progesterone antagonizes estradiol's effect on these behaviors. In a companion study, pubertal and post-pubertal females were similar for receptivity but pubertal females spent less time near a mature male. This difference in proceptivity likely reflects a maturational change associated with sexual development in female pigs. Collectively, these observations in postpubertal, female pigs document that prolonged estrogen treatment will activate aggressive behaviors in association with reduced proceptivity and receptivity. Because these behavioral changes are reversible by 5 months after cessation of treatment, they are not the result of sexual differentiation.     

Effects of intracerebroventricular leptin administration on feeding and sexual behaviors in lean and obese female Zucker rats

Obese Zucker rats (fa/fa) are characterized by inadequate leptin signaling caused by a mutation in the leptin receptor gene. Obese Zucker females are infertile and hyporesponsive to the inductive effects of ovarian hormones on sexual behaviors. Leptin treatment reverses aspects of reproductive dysfunction due to perturbations in energy balance in other animal models. Our first experiment tested the hypothesis that intracerebroventricular (icv) leptin administration would enhance the display of sexual behaviors in obese Zucker females. A second experiment compared lean and obese Zucker females' responses to leptin, during fed and fasted conditions. Ovariectomized (OVX) Zucker rats were implanted with lateral ventricular cannulae. In Experiment 1, fasted, obese females received estradiol benzoate, progesterone, and icv injections of 3, 18, or 36 microg murine leptin or vehicle. Leptin administration reduced food intake, but did not enhance sexual behaviors. In Experiment 2, steroid-replaced, OVX lean and obese females (from a different source than those in Experiment 1) received icv injections of vehicle or 3 or 36 microg leptin under fed and fasted conditions. Leptin treatment reduced food intake and weight gain in the fed, but not the fasted, condition in both genotypes. Sexual receptivity and locomotion were not affected, but icv leptin injections reduced proceptive behaviors in ad libitum-fed rats. These data confirm previous reports that centrally administered leptin decreases food intake and weight gain in obese Zucker rats; results from Experiment 2 suggest that lean and obese females are similarly responsive to these actions of leptin. Contrary to our hypothesis, leptin treatment did not stimulate sexual behaviors; rather, the hormone appears to inhibit the display of sexual proceptivity in ad libitum-fed lean and obese Zucker female rats.     

The inhibitory actions of progesterone: effects on male and female sexual behavior of the hamster

A series of three experiments compared the inhibitory effects of progesterone on estrogen- or androgen-induced sexual behavior in male and female hamsters. In the first experiment chronic progesterone treatment was found to have no effect on male copulatory behavior maintained after castration with testosterone propionate or estradiol benzoate. However, testosterone propionate was more effective at maintaining male behavior than estradiol benzoate. In the second experiment progesterone was found to have a slight inhibitory effect on the rate of the restoration of the intromission response after androgen treatment in males which had been castrated for 8 weeks. In the final experiment, chronic progesterone treatment markedly inhibited sexual receptivity in male and female hamsters which had been given 4 weeks of androgen or estrogen treatment and a single pretest injection of progesterone. Thus, progesterone was shown to be a potent inhibitor of androgen- or estrogen-induced estrus in both male and female hamsters. Due to the large difference in effectiveness on these two behavioral systems, we suggest that progesterone affects steroid-induced male copulatory behavior and female receptivity by different mechanisms of action.     

Photoperiodic modulation of sexual and aggressive behavior in female golden hamsters (Mesocricetus auratus): role of the pineal gland

Pinealectomized female hamsters (Mesocricetus auratus) housed in a short-day photoperiod were ovariectomized and tested for hormone-induced sexual receptivity in order to investigate the role of the pineal gland in the control of behavioral sensitivity to exogenous ovarian steroid hormones (Experiment 1). Behavioral sensitivity to hormones was further investigated in females maintained in a long-day photoperiod and rendered acyclic by daily administration of exogenous melatonin (Experiment 2). Female aggressive behavior was also monitored in all tests. Pinealectomy did not affect the reduced behavioral sensitivity to exogenous estrogen (E) induced by short days. These animals were also partially refractory to the effects of E when combined with low doses of progesterone. In addition, although melatonin administration mimicked the effects of short days on estrous cyclicity, the expression of hormone-dependent behaviors in these animals resembled the pattern displayed by control animals kept in long days. Thus, these findings suggest that the pineal gland plays a negligible role in the photoperiodic modulation of hormone-dependent sociosexual behaviors in female hamsters.     

Systemic ICI 182,780 alters the display of sexual behaviors in the female rat

The present study investigates the effects of the antiestrogen ICI 182,780 (ICI) on the display of sexual behaviors in female rats. ICI 182,780 is a pure anti-estrogen and when given systemically, ICI is thought to act only in the periphery, and is not believed to cross the blood brain barrier. The present study examines the effects of ICI on sexual receptivity and on paced mating behavior following treatment with estradiol benzoate (EB) and progesterone (P) (Experiment 1) or with EB alone (Experiment 2). In Experiment 1, ICI (250.0 microg) did not affect the display of receptivity or paced mating behavior induced by EB and P. In contrast, in Experiment 2 female rats receiving EB alone displayed a decrease in the level of sexual receptivity following treatment with 500.0 and 750.0 microg ICI (but not 250.0 microg ICI). In addition, in Experiment 2 EB-treated female rats receiving 250.0 microg ICI spent more time away from the male rat following an intromission and were more likely to exit from the male compartment following a mount. Last, ICI had potent antiestrogenic effects on vaginal cytology (Experiment 2) and on the uterus (Experiments 1 and 2). The present study supports a role for peripheral estrogen receptors in sexual receptivity and paced mating behavior and suggests that estrogen receptor activation may decrease the aversive sensation associated with sexual stimulation.     

Early androgen treatment and male and female sexual behavior in mice

To investigate the role of neonatal androgen stimulation in the development of the potential for masculine and feminine sexual behavior in the mouse, different groups of mice were hormonally manipulated early in life. One group of female mice was administered testosterone propionate (TP) within 24 hr of birth; a second group of females was given a control injection of oil on the day of birth; a third group of females received an injection of TP on the 10th day after birth. A group of males received a control injection of oil on the day of birth. All mice were gonadectomized at about 30 days of age. At 60 days of age, mice were injected with estrogen and progesterone and tested for sexual receptivity; several weeks later all mice were injected with TP and tested for male sexual behavior. Female behavior: Females given oil at birth and females given TP on the 10th day after birth showed high levels of sexual receptivity as adults following estrogen-progesterone treatment. Females given TP on the day of birth, and male mice, rarely exhibited lordosis following estrogen-progesterone treatment. Male behavior: Most mice, regardless of genetic sex or neonatal treatment, mounted in adulthood following administration of exogenous androgen. There was little difference in mounting frequency between groups, suggesting that exogenous or endogenous androgen stimulation of the neonatal mouse does not facilitate adult mounting behavior. These data for the mouse are in essential agreement with existing data for the rat, and indicate that sexual behavioral differentiation induced by androgen stimulation in infancy is best characterized as an inhibition of the potential to display feminine sexual behavior in adulthood.     

Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.     

Hysterectomy-induced facilitation of lordosis behavior in the rat

The present study investigated the effect of hysterectomy on hormone-induced lordosis behavior. Lordosis quotients (LQ) were measured in hysterectomized-ovariectomized (HO) and ovariectomized-sham hysterectomized (OSH) rats after several treatments including either estradiol benzoate (EB) alone or EB plus progesterone (P) 44 hr later. Testing consisted of placing the females with sexually active males 48 hr after EB. In Experiment 1, HO animals treated with 5 μg/kg EB and 0.5 mg P had significantly higher LQs than OSH animals; groups treated with 10 μg/kg plus P were not different. Experiment 2 showed that a single injection of 50 μg/kg EB resulted in equally high levels of receptivity in both groups. The LQs of HO animals injected with 3 μg/kg for 4 days did not differ from those of OSH animals; however, the administration of 0.5 mg P 24 hr after the fourth EB injection resulted in significantly higher LQs in the HO group (Experiment 3). In Experiment 4, HO rats injected with 5 μg/kg EB and 0.1 mg P 44 hr later displayed higher levels of lordosis behavior than OSH animals. It was concluded that hysterectomy facilitated the lordosis behavior of ovariectomized rats injected with both EB and P and that the mechanism for this potentiation remains to be determined.     

Acute and chronic stress-like levels of cortisol inhibit the oestradiol stimulus to induce sexual receptivity but have no effect on sexual attractivity or proceptivity in female sheep

Stress-like levels of cortisol inhibit sexual receptivity in ewes but the mechanism of this action is not understood. One possibility is that cortisol interferes with the actions of oestradiol to induce sexual receptivity. We tested this hypothesis in 2 experiments with ovariectomised ewes that were artificially induced into oestrus by 12 days of i.m. injections of progesterone followed by an i.m. injection of oestradiol benzoate (ODB) 48 h later. In Experiment 1, ewes were randomly allocated to the following groups: saline infusion + 25 μg ODB, saline infusion + 50 μg ODB, cortisol infusion + 25 μg ODB or cortisol infusion + 50 μg ODB (n = 5 per group). Saline or cortisol was infused i.v. for 40 h beginning at the ODB injection. In Experiment 2, ewes were infused with saline or cortisol (n = 5 per group) for 5 h beginning 1 h before ODB injection. In both experiments, ewe sexual behaviour (attractivity, proceptivity and receptivity) was quantified every 6 h. Blood samples were also collected. The cortisol infusion yielded plasma concentrations of cortisol similar to those seen during psychosocial stress. In both experiments, cortisol suppressed receptivity index (number of immobilisations by ewe/courtship displays by ram) and the number of times ewes were mounted but had no effect on attractivity or proceptivity, irrespective of the dose of ODB (Experiment 1). Cortisol also suppressed LH pulse amplitude. These results suggest that both an acute (5 h) and chronic (40 h) infusion of cortisol inhibit oestradiol-induced sexual receptivity in ewes and that increasing the dose of ODB does not overcome the inhibitory effects of cortisol.     

Sensitivity to corticosterone-induced cleft palate is not associated with H-2

The frequency of cleft palate (CP) and corticosterone levels in maternal plasma and amniotic fluid were determined in pregnant C57BL/10 (H-2b) and congenic B10.A (H-2a) mice after the ip injection of repository ACTH, corticosterone acetate, or desoxycorticosterone acetate (DOCA) on the 11th through 14th day of gestation. It was found that ACTH (a) induces CP in B10.A but not C57BL/10 mice, (b) induces CP in B10.A mice at about the same frequency noted when diluent alone is injected, and (c) produces an elevation in maternal plasma corticosterone levels 1.5- to 2.0-fold lower and amniotic fluid levels 3- to 5-fold lower than those found after the injection of 5 mg corticosterone acetate, a dose which induces a comparable frequency of CP in B10.A mice. The injection of 5 mg corticosterone acetate produced CP frequencies in C57BL/10 and B10.A mice of 4.9 and 3.3%, respectively, and increasing the dose to 9.2 mg resulted in significant increases in CP to 23.8 and 24.7%, respectively. DOCA at two dose levels induced CP in B10.A fetuses at about the frequency noted when diluent alone has been given. These findings show that susceptibility to corticosterone induced CP is not associated with the major histocompatibility complex of the mouse, H-2, as is the case with glucocorticoids (e.g., cortisone, dexamethasone), and they raise the possibility that factors other than or in addition to corticosterone may be involved in spontaneous or ACTH- or stress-induced CP.