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Menopausal women may experience symptoms of depression, sometimes even progressing clinical depression requiring treatment to improve quality of life. While varying levels of estrogen in perimenopause may contribute to an increased biological vulnerability to mood disturbances, the effectiveness of estrogen replacement therapy (ERT) in the relief of depressive symptoms remains controversial. Menopausal depression has a complex, multifactorial etiology, that has limited the identification of optimal treatment strategies for the management of this psychiatric complaint. Nevertheless, clinical evidence increasingly supports the notion that estrogen exerts neuroprotective effects on brain structures related to mood regulation. Indeed, research using preclinical animal models continues to improve our understanding of menopause and the effectiveness of ERT and other substances at treating depression-like behaviors. However, questions regarding the efficacy of ERT in perimenopause have been raised. These questions may be answered by further investigation using specific animal models of reduced ovarian function. This review compares and discusses the advantages and pitfalls of different models emulating the menopausal stages and their relationship with the onset of depressive-like signs, as well as the efficacy and mechanisms of conventional and novel ERTs in treating depressive-like behavior. Ovariectomized young rats, middle-to-old aged intact rats, and females treated with reprotoxics have all been used as models of menopause, with stages ranging from surgical menopause to perimenopause. Additionally, this manuscript discusses the impact of organistic and therapeutic variables that may improve or reduce the antidepressant response of females to ERT. Findings from these models have revealed the complexity of the dynamic changes occurring in brain function during menopausal transition, reinforcing the idea that the best approach is timely intervention considering the opportunity window, in addition to the careful selection of treatment according to the presence or absence of reproductive tissue. Additionally, data from animal models has yielded evidence to support new promising estrogens that could be considered as ERTs with antidepressant properties and actions in endocrine situations in which traditional ERTs are not effective.
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Elevated levels of endogenous ovarian hormones are conditions commonly experienced by women undergoing assisted reproductive technologies (ART). Additionally, infertility-associated stress and treatment routines are factors that together may have a highly negative impact on female emotionality, which can be aggravated when several cycles of ART are needed to attempt pregnancy. This study aimed to investigate the effect of high and fluctuating levels of gonadal hormones induced by repeated ovarian stimulation on the stress response in rodents. To mimic the context of ART, female rats were exposed to an unpredictable chronic mild stress (UCMS) paradigm for four weeks. During this time, three cycles of ovarian stimulation (superovulation) (150 IU/Kg of PMSG and 75 IU/Kg of hCG) were applied, with intervals of two estrous cycles between them. The rats were distributed into four groups: Repeated Superovulation/UCMS; Repeated Superovulation/No Stress; Saline/UCMS; and Saline/No Stress. Anxiety-like and depressive-like behaviors were evaluated in a light-dark transition box and by splash test, respectively. Corticosterone, estradiol, progesterone, and biometric parameters were assessed. Data were analyzed using a two-way Generalized Linear Model (GzLM). Our results showed that repeated ovarian stimulation exerts by itself an expressive anxiogenic effect. Surprisingly, when high and fluctuating levels of ovarian hormones were combined with chronic stress, anxiety-like behavior was no longer observed, and a depressive-like state was not detected. Our findings suggest that females subjected to emotional overload induced by repeated ovarian stimulation and chronic stress seem to trigger the elaboration of adaptive coping strategies.
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Corticosterona , Roedores , Animais , Ansiedade , Feminino , Humanos , Indução da Ovulação , Gravidez , Progesterona/farmacologia , RatosRESUMO
During puberty, sexual hormones induce crucial changes in neural circuit organization, leading to significant sexual dimorphism in adult behaviours. The ventrolateral division of the ventromedial nucleus of the hypothalamus (VMHvl) is the major neural site controlling the receptive component of female sexual behaviour, which is dependent on ovarian hormones. The inputs to the VMHvl, originating from the medial nucleus of the amygdala (MeA), transmit essential information to trigger such behaviour. In this study, we investigated the projection pattern of the MeA to the VMHvl in ovariectomized rats at early puberty. Six-week-old Sprague-Dawley rats were ovariectomized (OVX) and, upon reaching 90 days of age, were subjected to iontophoretic injections of the neuronal anterograde tracer Phaseolus vulgaris leucoagglutinin into the MeA. Projections from the MeA to the VMHvl and to other structures included in the neural circuit responsible for female sexual behaviour were analysed in the Control and OVX groups. The results of the semi-quantitative analysis showed that peripubertal ovariectomy reduced the density of intra-amygdalar fibres. The stereological estimates, however, failed to find changes in the organization of the terminal fields of nerve fibres from the MeA to the VMHvl in the adult. The present data show that ovariectomized rats during the peripubertal phase did not undergo significant changes in MeA fibres reaching the VMHvl; however, they suggest a possible effect of ovariectomy on MeA connectivity under amygdalar subnuclei.
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Complexo Nuclear Corticomedial/metabolismo , Rede Nervosa/metabolismo , Ovariectomia/tendências , Maturidade Sexual/fisiologia , Núcleo Hipotalâmico Ventromedial/metabolismo , Fatores Etários , Animais , Complexo Nuclear Corticomedial/diagnóstico por imagem , Feminino , Imageamento Tridimensional/tendências , Rede Nervosa/diagnóstico por imagem , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Ovariectomia/efeitos adversos , Ratos , Ratos Sprague-Dawley , Núcleo Hipotalâmico Ventromedial/diagnóstico por imagemRESUMO
BACKGROUND: Normotensive premenopausal women show a vagal predominance of cardiac autonomic modulation, whereas age-matched men show a predominance of sympathetic modulation. However, some women develop systemic arterial hypertension (SAH) even with preserved ovarian function. Our hypothesis is that these women may have cardiovascular autonomic parameters similar to those of hypertensive men, even when subjected to pharmacological treatment. We aimed to investigate cardiovascular autonomic control and baroreflex sensitivity (BRS) in hypertensive premenopausal women and age-matched men. METHODS: One hundred volunteers between 18 and 45 years of age were assigned to two groups (50 participants each): a hypertensive group including patients with a history of SAH for at least 6 months (25 men and 25 women), who were under treatment with monotherapy (losartan, 25-50 mg/kg); and a normotensive group (25 men and 25 women). Anthropometric, hemodynamic, metabolic, and autonomic cardiovascular assessments were performed focusing on BRS, autonomic modulation of heart rate variability (HRV), and blood pressure variability (BPV). RESULTS: On HRV analysis, women showed higher values of high-frequency (HF) oscillations in absolute and normalized units, lower values âof low-frequency (LF) in normalized units, and lower LF/HF ratio, as compared with men. When the normotensive and hypertensive groups were compared, hypertensive groups showed lower values âof total variance and of LF and HF bands in absolute units. On BRS, hypertensive groups showed lower values than the normotensive group. CONCLUSION: Regardless of blood pressure control through pharmacological treatment, hypertensive patients continued to have reduced HRV compared to normotensive, and hypertensive men had more autonomic impairment than hypertensive premenopausal women.
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Hipertensão , Caracteres Sexuais , Adolescente , Adulto , Sistema Nervoso Autônomo , Barorreflexo , Feminino , Frequência Cardíaca , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
ABSTRACT Objective: Staphylococcus aureus infections remain associated with considerable morbidity and mortality in both hospitals and the community. There is little information regarding the role of ovarian hormones in infections caused by S. aureus. The aim of this study was to evaluate the effects of ovariectomy in the immune response induced by S. aureus. Methods: Female mice BALB/c were ovariectomized (OVX) to significantly reduce the level of ovarian hormones. We also used sham-operated animals. The mice were inoculated intraperitoneally with S. aureus. Blood samples were collected for leukocyte count and bacterial quantification. The uterus and spleen were removed and weighed to calculate the uterine and splenic indexes. Lungs were removed and fractionated for immunohistochemical analysis for macrophage detection (anti-CD68) and relative gene expression of IL-6, IL-1β and TNF-α by RT-PCR. Results: Ovariectomy enlarged spleen size and generally increased circulating lymphocytes. OVX females experienced a continuation of the initial reduction of lymphocytes and a monocyte and neutrophil late response compared to shams (p ≥ 0.05). Moreover, OVX females showed neutropenia after 168 h of infection (p ≥ 0.05). Macrophage response in the lungs were less pronounced in OVX females in the initial hours of infection (p ≥ 0.01). OVX females showed a higher relative gene expression of IL-1β, IL-6 and TNF-α in the lung at the beginning of the infection compared to sham females (p ≥ 0.01). Among the uninfected females, the OVX control females showed a higher expression of IL-6 in the lung compared to the sham control females (p ≥ 0.05). In this model, the lack of ovarian hormones caused a minor increase in circulating leukocytes during the initial stage of infection by S. aureus and increased pulmonary gene expression of IL-1β, IL-6, and TNF-α. Ovariectomy alone enlarged the spleen and increased circulating lymphocytes. Ovarian hormones acted as immunoprotectors against S. aureus infection.
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Animais , Feminino , Humanos , Camundongos , Infecções Estafilocócicas , Staphylococcus aureus , Hormônios , Imunidade , Camundongos Endogâmicos BALB CRESUMO
OBJECTIVE: Staphylococcus aureus infections remain associated with considerable morbidity and mortality in both hospitals and the community. There is little information regarding the role of ovarian hormones in infections caused by S. aureus. The aim of this study was to evaluate the effects of ovariectomy in the immune response induced by S. aureus. METHODS: Female mice BALB/c were ovariectomized (OVX) to significantly reduce the level of ovarian hormones. We also used sham-operated animals. The mice were inoculated intraperitoneally with S. aureus. Blood samples were collected for leukocyte count and bacterial quantification. The uterus and spleen were removed and weighed to calculate the uterine and splenic indexes. Lungs were removed and fractionated for immunohistochemical analysis for macrophage detection (anti-CD68) and relative gene expression of IL-6, IL-1ß and TNF-α by RT-PCR. RESULTS: Ovariectomy enlarged spleen size and generally increased circulating lymphocytes. OVX females experienced a continuation of the initial reduction of lymphocytes and a monocyte and neutrophil late response compared to shams (p≥0.05). Moreover, OVX females showed neutropenia after 168h of infection (p≥0.05). Macrophage response in the lungs were less pronounced in OVX females in the initial hours of infection (p≥0.01). OVX females showed a higher relative gene expression of IL-1ß, IL-6 and TNF-α in the lung at the beginning of the infection compared to sham females (p≥0.01). Among the uninfected females, the OVX control females showed a higher expression of IL-6 in the lung compared to the sham control females (p≥0.05). In this model, the lack of ovarian hormones caused a minor increase in circulating leukocytes during the initial stage of infection by S. aureus and increased pulmonary gene expression of IL-1ß, IL-6, and TNF-α. Ovariectomy alone enlarged the spleen and increased circulating lymphocytes. Ovarian hormones acted as immunoprotectors against S. aureus infection.
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Infecções Estafilocócicas , Staphylococcus aureus , Animais , Feminino , Hormônios , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The severe acute respiratory syndrome due to coronavirus 2 (SARS-CoV-2) infection has affected millions of individuals worldwide, causing high mortality rates and severe physical sequelae, with a negative impact on society, economy, health care, lifestyle and personal relationships. Studies have confirmed this infection has sex and age differences in terms of disease severity and immune response, with a particular relationship with the anti-Müllerian hormone, a marker of aging, and estradiol, a marker of ovarian function. Postmenopausal women seem to present a more severe infection as compared to premenopausal ones. Estradiol protects the vascular system, mediating with the renin-angiotensin-aldosterone system, whereas testosterone enhances the levels of angiotensin-converting enzyme and the transmembrane protease serine-type 2, thus delaying viral clearance in men as compared to women. This new infection will stay among us, transforming our social, economic and daily lifestyle, and hence medical and health care as well as the use of menopause hormone therapy will need redefining, considering both preventive and curative perspectives.
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COVID-19/metabolismo , Pós-Menopausa/metabolismo , SARS-CoV-2/metabolismo , Saúde da Mulher , COVID-19/epidemiologia , Feminino , Nível de Saúde , Humanos , Pessoa de Meia-Idade , Peptidil Dipeptidase A/metabolismoRESUMO
Studies have presented conflicting findings regarding the association between both fluctuation and deprivation of ovarian hormones and cardiovascular autonomic modulation and oxidative stress and their potential impact on resting arterial pressure (AP) and cardiovascular risk. This study aimed to assess cardiovascular autonomic modulation, baroreflex sensitivity (BRS), and oxidative stress in male rats (M) and in female rats during ovulatory (FOV) and non-ovulatory phases (FNOV) of the estrous cycle and after deprivation of ovarian hormones (FO). Direct AP was recorded, and BRS was assessed by using increasing doses of phenylephrine and sodium nitroprusside. AP and heart rate variability were assessed by spectral analysis. Oxidative stress profile was evaluated in cardiac, renal, and muscle tissues. In females, the ovulatory phase and ovarian hormone deprivation induced an increase in AP (FOV and FO ~ 9 mmHg) when compared to the non-ovulatory phase. Ovariectomy promoted increased cardiac sympathovagal balance (~ 17-37%) when compared to other groups. Both FOV and FO groups presented impaired BRS, associated with higher AP variability. In general, antioxidant capacity was higher in the FNOV than in the M group. Ovarian hormone deprivation induced a decrease in catalase activity in cardiac and renal tissues and an increase in lipid peroxidation in all tissues analyzed. Positive correlations (p < 0.05) were found between vascular sympathetic modulation and lipid peroxidation in cardiac (r = 0.60), renal (r = 0.60), and muscle (r = 0.57) tissues. In conclusion, both oscillation and deprivation of ovarian hormones play an important role in cardiovascular autonomic control and oxidative stress profile in target organs, which is reflected in AP changes.
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Ovário/fisiologia , Estresse Oxidativo , Animais , Pressão Arterial , Barorreflexo , Ciclo Estral , Feminino , Masculino , Ovariectomia , Ratos WistarRESUMO
Astroglial cells are crucial for central nervous system (CNS) homeostasis. They undergo complex morpho-functional changes during aging and in response to hormonal milieu. Ovarian hormones positively affect different astroglia parameters, including regulation of cell morphology and release of neurotrophic and neuroprotective factors. Thus, ovarian hormone loss during menopause has profound impact in astroglial pathophysilogy and has been widely associated to the process of brain aging. Humanin (HN) is a secreted mitochondrial-encoded peptide with neuroprotective effects. It is localized in several tissues with high metabolic rate and its expression decreases with age. In the brain, humanin has been found in glial cells in physiological conditions. We previously reported that surgical menopause induces hippocampal mitochondrial dysfunction that mimics an aging phenotype. However, the effect of ovarian hormone deprivation on humanin expression in this area has not been studied. Also, whether astrocytes express and release humanin and the regulation of such processes by ovarian hormones remain elusive. Although humanin has also proven to be beneficial in ameliorating cognitive impairment induced by different insults, its putative actions on structural synaptic plasticity have not been fully addressed. In a model of surgical menopause in rats, we studied hippocampal humanin expression and localization by real-time quantitative polymerase chain reaction (RT-qPCR) and double immunohistochemistry, respectively. Humanin production and release and ovarian hormone regulation of such processes were studied in cultured astrocytes by flow cytometry and ELISA, respectively. Humanin effects on glutamate-induced structural synaptic alterations were determined in primary cultures of hippocampal neurons by immunocytochemistry. Humanin expression was lower in the hippocampus of ovariectomized rats and its immunoreactivity colocalized with astroglial markers. Chronic ovariectomy also promoted the presence of less complex astrocytes in this area. Ovarian hormones increased humanin intracellular content and release by cultured astrocytes. Humanin prevented glutamate-induced dendritic atrophy and reduction in puncta number and total puncta area for pre-synaptic marker synaptophysin in cultured hippocampal neurons. In conclusion, astroglial functional and morphological alterations induced by chronic ovariectomy resemble an aging phenotype and could affect astroglial support to neuronal function by altering synaptic connectivity and functionality. Reduced astroglial-derived humanin may represent an underlying mechanism for synaptic dysfunction and cognitive decline after menopause.
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OBJECTIVES: We investigated the effects of early ovarian hormones deprivation on morphology and cardiac function and the effects of aerobic training on these parameters, in old rats. METHODS: Female Wistar rats (Nâ¯=â¯48) were divided into two groups, at 10â¯weeks of life: early ovarian hormones deprivation by ovariectomy (OVX; Nâ¯=â¯24) and sham (SHAM; Nâ¯=â¯24). Between weeks 62 and 82, 12 animals of each group underwent aerobic training (OVX-T and SHAM-T, Nâ¯=â¯12). At the end of week 82, all were evaluated by echocardiography, cardiac function (Langendorff technique) and cardiac ß-adrenergic receptor expression quantification. RESULTS: Echocardiography showed slight changes in morphology between OVX and SHAM groups. OVX group (Δâ¯=â¯101⯱â¯4.7â¯mmHg) showed higher values for maximal left intraventricular pressure in response to dobutamine, when compared to SHAM group (Δâ¯=â¯55⯱â¯11.8â¯mmHg). Both OVX-T (Δâ¯=â¯70⯱â¯4.0â¯mmHg) and SHAM-T (Δâ¯=â¯22⯱â¯6.6â¯mmHg) groups showed a reduction in this response. While, ß-adrenergic receptor expression was not different between the untrained groups, SHAM-T (0.23⯱â¯0.02â¯AU) and OVX-T (0.29⯱â¯0.01â¯AU), showed decreased expression of these receptors. CONCLUSION: Early ovarian hormones deprivation associated with aging, promotes discrete changes in cardiac morphology and increasing cardiac contractility. Aerobic training decreases ß-adrenergic receptors expression, influencing the cardiac contractility.
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Hormônios Esteroides Gonadais/fisiologia , Coração/fisiologia , Contração Miocárdica/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Ecocardiografia , Feminino , Ovariectomia , Ratos Wistar , Receptores Adrenérgicos beta/fisiologia , Pressão VentricularRESUMO
OBJECTIVES: Ovarian hormones (OH) and early malnutrition may affect the developing brain, with repercussions on behavioral and excitability-dependent processes. However, the possible synergistic effects of both factors have not been analyzed. In this study, we investigated the effect of treatment in early life with OH and suckling among distinct litter sizes on recognition memory, anxiety behavior, and the excitability-dependent phenomenon known as cortical spreading depression (CSD). METHODS: Female Wistar rats were suckled under favorable and unfavorable lactation, corresponding to litters with 9 and 15 pups (L9 and L15 groups, respectively). From postnatal days (P) 7 to 21, the animals received 50â µg/kg of ß-estradiol or progesterone. From P80 to P84, we tested behavioral reactions. From P90 to P120, we analyzed CSD parameters. RESULTS: Compared with the corresponding L9 groups, the OH-treated L15 groups performed worse in recognition memory tasks. No intergroup difference in the anxiety parameters was observed. Compared with naive and vehicle-treated controls, OH-treated groups displayed higher CSD velocities and amplitudes and shorter CSD durations. DISCUSSION: Early treatment with OH facilitates recognition memory and CSD, and in association with unfavorable lactation (L15) impaired recognition memory, but not anxiety behavior, in the adult brain. OH treatment and L15 lactation condition seem to interact regarding OH action on memory, but not on CSD. Data suggest a long-lasting differential effect that might be related to the lasting hormonal action on brain excitability. We postulate and discuss the possibility that these findings may be implicated in human neurological diseases.
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Encéfalo/fisiologia , Depressão Alastrante da Atividade Elétrica Cortical , Estradiol/fisiologia , Lactação , Progesterona/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Animais Recém-Nascidos , Animais Lactentes , Ansiedade , Comportamento Animal , Estradiol/administração & dosagem , Feminino , Tamanho da Ninhada de Vivíparos , Masculino , Progesterona/administração & dosagem , Ratos WistarRESUMO
We investigated the effects of angiotensin-converting enzyme (ACE) inhibition and aerobic physical training on the heart of old female rats (82-wk-old) submitted to premature ovarian failure (10-wk.-old). We used different approaches: morphology and function by echocardiography, reactivity of the coronary bed and left ventricular contractibility (Langendorff Technique). Female Wistar ovariectomized (OVX) rats (n=42) were assigned to one of four groups: OVX, vehicle treated only; OVX-EM, Enalapril Maleate only (EM, 10mg·kg-1·d-1); OVX-T, aerobic trained only; and OVX-EMT, treated with Enalapril Maleate and aerobic trained. Both Enalapril Maleate treatment and aerobic training were done in the last 20weeks of the experimental protocol. When compared to the OVX group, the OVX-EM group showed lower values of wall thickness and left ventricular (LV) mass, lower values of coronary bed reactivity and reduced maximum response of LV contractility to dobutamine, while the OVX-T group showed lower values of LV wall thickness, increase in end-systolic volume, reduced maximum response of LV contractility to dobutamine, and left intraventricular pressure due to increased flow. The combination of treatments (EM and aerobic physical training) did not promote additional important effects on the parameters evaluated. Our results suggest similar beneficial effects of physical training and EM treatment on the morphology and cardiac function in old female rats submitted to premature ovarian failure. Although the causes of these benefits are still unknown, both treatments have promoted a decrease in cardiac contractility, and the reduced ß1-adrenergic sensitivity suggests that both treatments may attenuate the sympathetic effect on the heart.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalapril/farmacologia , Coração/efeitos dos fármacos , Condicionamento Físico Animal , Insuficiência Ovariana Primária/fisiopatologia , Animais , Feminino , Coração/fisiologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/patologia , Ovariectomia , Insuficiência Ovariana Primária/patologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/fisiologia , Função Ventricular EsquerdaRESUMO
BACKGROUND: We investigated whether the treatment with enalapril maleate, combined with aerobic physical training, promotes positive effects on the autonomic balance, the morphology and the cardiac function in female rats submitted to early ovarian failure. METHODS: Thirty-five female Wistar rats, ovariectomized at 10weeks of age, were assigned into Ovariectomized rats (OVX) and Ovariectomized rats treated with enalapril maleate (OVX-EM, 10mg-1·kg-1·d-1) Each group was subdivided into sedentary and trained (aerobic swimming training for 10weeks). All animals were submitted to a) double pharmacological autonomic blockade, b) study of morphology and cardiac function by echocardiography, and c) analysis of cardiac fibrosis. RESULTS: The OVX-EM sedentary group showed a significant increase in cardiac fibrosis, relative heart weight, interventricular septum thickness and increased sympathetic participation and reduced participation of the vagal tone in the determination of the basal heart rate when compared to the OVX sedentary group. Physical training reduced cardiac fibrosis in both groups, however, with less intensity in the OVX-EM group. It also increased the absolute and relative heart weight and the end-systolic volume. Finally, the OVX-EM trained group showed higher values for left ventricular end-systolic volume and lower values for ejection fraction and shortening fraction than the sedentary OVX-EM group. CONCLUSION: Enalapril maleate exacerbated cardiac fibrosis and increased sympathetic participation in the basal heart rate determination, without significantly affecting the cardiac function. Aerobic physical training did not change the cardiac autonomic control, but reduced cardiac fibrosis and had little effect on the cardiac function.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalapril/farmacologia , Cardiopatias/fisiopatologia , Doenças Ovarianas/fisiopatologia , Condicionamento Físico Animal , Animais , Modelos Animais de Doenças , Ecocardiografia , Terapia por Exercício , Feminino , Fibrose/diagnóstico por imagem , Fibrose/patologia , Fibrose/fisiopatologia , Fibrose/terapia , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias/diagnóstico por imagem , Cardiopatias/patologia , Cardiopatias/terapia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Miocárdio/patologia , Tamanho do Órgão , Doenças Ovarianas/patologia , Doenças Ovarianas/terapia , Ovariectomia , Ratos Wistar , NataçãoRESUMO
Hormones highly influence female behaviors. However, research on this topic has not usually considered the variable hormonal status. The prelimbic cortex (PrL) is commonly engaged in fear learning. Connections from and to this region are known to be critical in regulating anxiety, in which serotonin (5-HT) plays a fundamental role, particularly through changes in 5-HT1A receptors functioning. Also, hormone fluctuations can greatly influence anxiety in humans and anxiety-related behavior in rodents, and this influence involves the functioning of 5-HT brain systems. The present investigation sought to determine whether fluctuations in ovarian hormones relative to the estrous cycle would influence the expression of learned fear in female rats previously selected as low- (LA) or high-anxious (HA). Furthermore, we investigate the role of the 5-HT system of the PrL, particularly the 5-HT1A receptors, as a possible modulator of estrous cycle influence on the expression of learned fear through intra-PrL microinjections of 5-HT itself or the full 5-HT1A agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamine)tetralin). Behavioral changes were assessed using the fear-potentiated startle (FPS) procedure. The results showed that fear intensity is associated with hormonal decay, being more accentuated during the estrus phase. This increase in fear levels was found to be negatively correlated with the expression of potentiated startle. In rats prone to anxiety and tested during the proestrus and estrus phases, 5-HT mechanisms of the PrL seem to play a regulatory role in the expression of learned fear. These results were not replicated in the LA rats. Similar but less intense results were found regarding the early and late diestrus. Our data indicate that future studies on this subject need to take into account the dissociation between low- and high-responsive females to understand how hormones affect emotional behavior.