High and fluctuating levels of ovarian hormones induce an anxiogenic effect, which can be modulated under stress conditions: Evidence from an assisted reproductive rodent model.

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.

A single ovarian stimulation, as performed in assisted reproductive technologies, can modulate the anxiety-like behavior and neuronal activation in stress-related brain areas in rats.

Infertility affects about 8 to 12% of couples of childbearing age around the world, and is recognized as a global public health issue by the WHO. From a psychosocial perspective, infertile individuals experience intense psychological distress, related to emotional disorders, which have repercussions on marital and social relationships. The symptoms persist even after seeking specialized treatment, such as assisted reproductive technologies (ART). While the stress impact of ART outcome has been comprehensively studied, the role of supraphysiological concentrations of gonadal hormones on stress response, remains to be elucidated. This study aimed to evaluate the effect of a single ovarian stimulation on the stress response in rats. To mimic the context of ART in rodents, female rats were submitted to the superovulation (150 UI/kg of PMSG and 75 UI/kg of hCG) and then to psychogenic stress (restraint stress for 30 min/day, repeated for three days). Anxiety-like behavior was evaluated in the elevated plus-maze, and neuronal activation in the stress-related brain areas assessed by Fos protein immunoreactivity. Corticosterone, estradiol, progesterone and corpora lutea were quantified. Data were analyzed using Generalized Linear Model (GzLM). Our findings indicate anxiolytic-like and protective effects of supraphysiological concentrations of gonadal hormones induced by a single ovarian stimulation on stress response. An activation of hypothalamus-pituitary-adrenal response inhibitory pathways, with participation of the prefrontal cortex, basomedial amygdala, lateral septum, medial preoptic area, dorsomedial and paraventricular hypothalamus, was detected.

Lactulose decreases neuronal activation and attenuates motor behavioral deficits in hyperammonemic rats.

Lactulose is a nonabsorbable disaccharide commonly used in clinical practice to treat hepatic encephalopathy. However, its effects on neuropsychiatric disorders and motor behavior have not been fully elucidated. Male Wistar rats were bile-duct ligated, and 3 weeks after surgery, treated with lactulose administrated by gavage (1.43 or 3.57 g/kg), once a day for seven days. Plasma levels of ammonia, aspartate aminotransferase, total bilirubin, and creatinine were quantified and histopathological analysis of the livers was performed. Locomotor activity measurements were performed in an open field. The expression of water channel aquaporin-4 was investigated and the analysis of Fos protein immunoreactivity was used to evaluate the pattern of neural activation in brain areas related to motor behavior. Bile-duct ligated rats showed hyperammonemia, loss of liver integrity and function, impaired locomotor activity, reduced aquaporin-4 protein expression, and neuronal hyperactivity. Lactulose treatment was able to reduce ammonia plasma levels, despite not having an effect on biochemical parameters of liver function, such as aspartate aminotransferase activity and total bilirubin levels, or on the cirrhotic hepatic architecture. Lactulose was also able to reduce the locomotor activity impairments and to mitigate or reverse most changes in neuronal activation. Lactulose had no effect on reduced aquaporin-4 protein expression. Our findings confirm the effectiveness of lactulose in reducing hyperammonemia and neuronal hyperactivity in brain areas related to motor behavior, reinforcing the importance of its clinical use in the treatment of the symptoms of cirrhosis-associated encephalopathy.