The estrous cycle in the dog: a review

Clinical, morphologic and hormonal changes throughout the estrous cycle in the dog are discussed in relation to the well established stages in this species — proestrus, estrus, metestrus and anestrus. Although most efforts in the past have been devoted to the period of reproduction, events throughout the remaining months of the cycle are presented to characterize the dog as a monocyclic animal in contrast to polycyclic species.     

Reproductive senescence in female rats: a longitudinal study of individual differences in estrous cycles and behavior

The longitudinal pattern of reproductive senescence was described in individual female rats from 4 to 18-22 mo of age. There were two subgroups of rats with different patterns of aging. The Constant Estrus (CE) subgroup progressed through regular cycles, irregular cycles, and constant estrus, followed by a return to irregular cycles, and then persistent diestrus. In contrast, the Irregular subgroup skipped constant estrus, maintaining irregular cycles until they entered persistent diestrus. In both subgroups, irregular cycles were a transition between the major reproductive states, although the type of transition was different in each subgroup. In the CE subgroup, the transition was gradual, continuous, and began with the onset of irregular cycles. In contrast, in the Irregular subgroup, the transition did not begin until the end of irregular cycles, suggesting that the process of aging was delayed. Most rats entered constant lordosis, a state characterized by a strong lordosis reflex that could be elicited by manual palpation on each day. The CE subgroup maintained the state once they entered it, whereas the Irregular subgroup intermittently returned to a lordosis reflex intensity characteristic of young rats. In addition, in the CE subgroup, but not the Irregular subgroup, changes in lordosis reflex intensity during aging were coupled to changes in the proportion of estrogenized vaginal smears during the cycle.     

Influence of the estrous cycle on hypoxic failure in the female rat heart

Background: Clinical studies have shown that fluctuation in the plasma concentrations of estrogen during the menstrual cycle has an effect on myocardial health in premenopausal women. When estrogen levels are low, the number of ischemic events experienced is increased.Objective: To determine whether the increased ischemic events reported with low plasma estrogen concentrations in women could be reproduced in an animal model, cardiac function was measured during hypoxia in the female rat at different time points of the estrous cycle.Methods: Hearts from female Sprague-Dawley rats were perfused in the working mode at the diestrous (low estrogen; n = 7) and proestrous (high estrogen; n = 6) phases of the estrous cycle, confirmed by plasma estradiol concentrations. Hearts were perfused under aerobic conditions with 5.5 mM glucose, 100 μU/mL insulin, and 1.2 mM palmitate, followed by a 30-minute period of hypoxia with 95% N₂-5% CO₂ gassing.Results: There were no significant differences in heart function between diestrous and proestrous groups prior to hypoxia. However, hypoxia induced perturbations in function that were dependent on the estrous cycle. Reductions in left ventricular systolic and diastolic pressure occurred with hypoxia, but no significant differences in these pressures were observed between groups. Left ventricular pulse pressure and coronary flow also decreased significantly during hypoxia (both, P < 0.05), but hearts from the proestrous group maintained a significantly higher pulse pressure (P < 0.05). Hearts from the proestrous group also maintained significantly higher rates of coronary flow during hypoxia (P < 0.05), compared with hearts from the diestrous group. However, despite the effect of proestrus, correlation coefficients between plasma estradiol concentrations and indices of cardiac function were not significant.Conclusions: Our findings indicate that the estrous cycle of the female rat affects cardiac function during hypoxia. This model may be useful to study the impact of the estrous cycle on metabolic and cardiovascular function.     

Neuroendocrine regulation of estrous behavior in the rabbit: similarities and differences with the rat

In this review, we compare the neuroendocrine control of estrous behavior in the rabbit, a reflex ovulator, and the rat, a more commonly studied spontaneous ovulator. Although the hormonal control of estrous behavior in both species is similar, notable differences include the absence of a stimulatory effect of progesterone (P) on sexual behavior in the rabbit and the retention of sexual behavior in a substantial proportion of female rabbits after ovariectomy. The ventrolateral component of the ventromedial hypothalamus (VMH) and an adjacent region caudal to it appear to be critical estrogen (E)-responsive regions for lordosis in the rat and rabbit, respectively. In both species the effects of E and P are largely mediated by the genomic action of their receptors (ER and PR), and in both species E similarly regulates the expression of these receptors. The prolonged, E-stimulated estrous of the rabbit is terminated after mating by unknown mechanisms, while the brief estrous of the rat is triggered by the proestrous peak of P and terminated by both the decline in P and the downregulation of hypothalamic PR. In both species, P most likely inhibits estrous behavior during pregnancy, and postpartum estrous may be triggered by a stimulatory effect of E coinciding with the withdrawal of P-mediated inhibition. Estrous behavior is inhibited in both species during lactation, most likely by the suckling-induced inhibition of gonadotropin secretion. This comparative approach can reveal neuroendocrine mechanisms underlying estrous behavior that are common to all mammals, while highlighting evolutionary adaptations unique to each species.     

Progesterone restores stress induced inhibition of estrous behavior in rat

Exposure to a stressor (mild electrical shocks to foot, five times per episode, at 1800, 1830, 1900 and 1930 hrs of proestrus) coinciding with period of pre-ovulatory progesterone secretion in rats abolished estrous behavior as shown by the absence of lordosis response and a significant increase in rejection quotient compared to controls. These rats did not show spermatozoa in the vaginal smear next day morning in contrast to their presence in controls. On the other hand, rats treated with progesterone (a single injection, 500 microg in 0.1 ml olive oil at 1800 hr of proestrus) prior to exposure to stressor showed normal estrous behavior, as shown by significantly lower rejection quotient than rats exposed to stress alone, lordosis quotient similar to controls and presence of spermatozoa in the vaginal smear next day. The results, albeit indirectly, to the best of our knowledge, first time indicate that stress induced impaired steroidogenesis leads to suppression of estrous behavior.     

Reproductive experience alters anxiety-like behavior in the female rat

Reproductive experience (i.e. pregnancy and lactation) results in significant alterations in subsequent hormone levels in female rats. Several studies have demonstrated that circulating hormones can significantly affect anxiety-like behavior. Thus, the purpose of the present study was to determine whether reproductive experience induces alterations in anxiety-like behaviors in cycling female rats and in older, reproductively senescent rats. In Experiment 1, the elevated plus maze (EPM) was used to test young cycling (6-8 weeks post-weaning) and middle-aged (32-36 weeks post-weaning) primiparous rats and their age-matched nulliparous counterparts for anxiety-like responses. In Experiment 2, activity in the open field was used as an additional measure of anxiety-like behavior in young (proestrus) and middle-aged (constant estrus) primiparous and nulliparous rats. For Experiment 3, EPM testing was conducted in separate groups of young and middle-aged animals tested two weeks after ovariectomy. The results revealed that during proestrus, primiparous animals exhibited fewer anxiety-like behaviors on the EPM compared to nulliparous controls. In middle-aged animals, however, parity was associated with increased anxiety-like behavior. In the open field, young, non-lactating primiparous animals again exhibited fewer anxiety-like behaviors compared to nulliparous controls, an effect that was reversed in middle-aged animals. Effects of reproductive experience on the EPM in both age groups were eliminated by ovariectomy. Overall, the findings indicate that reproductive experience significantly alters anxiety-like behavior, effects that are influenced by the endocrine status and/or age of the female.     

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.     

GABAergic drugs and lordosis behavior in the female rat

Agents modifying GABAergic neurotransmission were administered to ovariectomized rats treated with different doses of estradiol benzoate (EB) + progesterone (P) or with EB alone. Hormone treatments were designed to induce an intermediate level of receptivity in order to be able to observe both stimulatory and inhibitory effects on lordosis behavior. Both the GABAA receptor agonist THIP and the GABAB receptor agonist baclofen inhibited lordosis behavior at doses from 20 and 5 mg/kg, respectively. The GABA transaminase inhibitor gamma-acetylen GABA (GAG) and the GABA agonist 3-aminopropanesulfonic acid had no effects, even when high doses were administered. The GABAA receptor antagonist bicuculline had no effect by itself nor did it block the effects of THIP. It is therefore suggested that the GABAA receptor is of slight importance in the control of lordosis behavior. No evidence could be found supporting the hypothesis that an interaction between P and GABA is important for hormone-induced receptivity. It does not appear likely that motor disturbances are responsible for the inhibitory effects of baclofen and THIP. The exact mechanism by which these drugs inhibit lordosis behavior is not clear at present.     

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.     

Progestin receptors and the activation of female reproductive behavior: A critical review

Gonadal steroid hormones act upon the central nervous system (CNS) to regulate a variety of behavioral and neuroendocrine functions. Much attention has been focused on the mechanisms by which steroids interact with the brain to coordinate mammalian reproduction, particularly their role in the activation of mating behavior and in the feedback control of gonadotropin release. For example, female rodent reproductive behavior is abolished within a day or two following gonadectomy (Powers, 1970) and can be restored in a dose-dependent manner by exogenously administered estradiol and progesterone ( Boling and Blandau, 1939; Beach, 1942; Whalen, 1974). The molecular mechanisms underlying steroid induction of female rodent sexual behavior have been extensively investigated (for recent reviews see Feder, Landau, and Walker, 1979; McEwen, Davis, Parsons, and Pfaff, 1979; McEwen, 1981; Feder, 1984). To date, however, there is little conclusive evidence regarding the details of the molecular mechanisms by which estradiol and progesterone facilitate estrous behavior.     

Nonphotic phase shifting in female Syrian hamsters: interactions with the estrous cycle

Nonphotic phase shifting of circadian rhythms was examined in female Syrian hamsters. Animals were stimulated at zeitgeber time 4.5 by either placing them in a novel running wheel or by transferring them to a clean home cage. Placement in a clean home cage was more effective than novel wheel treatment in stimulating large (> 1.5 h) phase shifts. Peak phase shifts (ca. 3.5 h) and the percentage of females showing large phase shifts were comparable to those found in male hamsters stimulated with novel wheels. The amount of activity induced by nonphotic stimulation and the amount of phase shifting varied slightly with respect to the 4-day estrous cycle. Animals tended to run less and shift less on the day of estrus. Nonphotic stimulation on proestrus often resulted in a 1-day delay of the estrous cycle reflected in animals' postovulatory vaginal discharge and the expression of sexual receptivity (lordosis). This delay of the estrous cycle was associated with large phase advances and high activity. These results extend the generality of nonphotic phase shifting to females for the first time and raise the possibility that resetting of circadian rhythms can induce changes in the estrous cycle.     

Induction of ear wiggling in the estrous female rat by gonadectomized rats treated with androgens and estrogens

Intact and gonadectomized male and female rats treated with estradiol and/or dihydrotestosterone were introduced into the cage of estrous female rats. For 3 min the number of periods with ear wiggling displayed by the estrous female and the total duration of the periods with ear wiggling were recorded. It was found that estrous females showed about twice as much ear wiggling in the presence of intact males as in the presence of gonadectomized male and female rats. However, gonadectomized male and female rats treated with dihydrotestosterone induced as much ear wiggling as intact males did. In contrast, administration of estradiol to the gonadectomized stimulus rats did not affect the rate of ear wiggling of the estrous females. Estrous females showed the lowest rate of ear wiggling in the presence of intact female rats. It has been suggested that dihydrotestosterone-treated male and female rats have an odor which sexually excites estrous female rats.     

Preference for an estrous female over a non-estrous female evinced by female rats requires dihydrotestosterone plus estradiol

The effects were studied of long-term treatment with testosterone metabolites (dihydrotestosterone, DHT, and estradiol, E2, in sc Silastic implants) on preference behavior of ovariectomized female rats for an estrous female over a non-estrous female. For measuring this behavior a residential plus-maze was used which harbored two ovariectomized “stimulus” females on the top of peripheral boxes, one of which was made estrus by injection of estradiol benzoate and progesterone. When both steroids (DHT plus E2) were circulating simultaneously they evoked preference for an estrous female, while neither steroid by itself sufficed. In earlier work with adult male rats castrated on the day of birth, E2 was effective in the absence of DHT. This sex difference, therefore, seems to have arisen before birth. Further, administration of DHT alone caused a profound lack of interest in both “stimulus” females, which cannot be fully explained by the reduced locomotor activity which has been found to be induced by DHT in earlier Studies.     

Effect of prenatal androgen treatment on maternal behavior in the female rat

The perinatal critical period when androgen suppresses the capacity of virgin female rats to display maternal behavior in response to pups in adulthood was studied. A single direct injection of a large dose of testosterone propionate (TP) to the fetuses on Days 19 or 21 of pregnancy, but not during the neonatal period, significantly suppressed maternal responses in females. Percentages of females with anovulatory ovaries were largest in groups treated with TP within 2 days after birth. It is suggested that the androgen-sensitive period of the maternal mediating systems in the female rat exists prenatally, whereas the critical period of the systems regulating the cyclic release of ovulatory hormone is in the neonatal period.