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.