Hypogonadism induces depressive-like behaviour and increases astrocytic expression, whereas hyperestrogenism prevents these effects: evidence from two pubertal rat models

Introduction

Imbalances in sex hormone levels during puberty are known to affect overall health. However, limited information is available regarding hormone therapy in the context of feminization. In veterinary medicine, there is no consensus on the optimal age for castration and its implications for animals’ quality of life. To address these gaps, the present study proposed two experimental models: a hypogonadism model in pubertal rats induced by castration, and a hyperestrogenism model induced by castration followed by estrogen administration.

Objectives

This study aimed to investigate pathophysiological and neurobiological mechanisms associated with hypogonadism and hyperestrogenism, as well as to establish an experimental model of hyperestrogenism in rats.

Methods

The study was approved by the Animal Ethics Committee (CEUA-UNIP; protocol no. 2302310522). Pubertal rats were assigned to the following groups: castrated (hypogonadism group, HG, n = 7), castrated and treated weekly with estrogen (estradiol cypionate, 200 µg/kg, subcutaneous [s.c.], for nine weeks; hyperestrogenism group, HE, n = 7), and a control group (CO, n = 7) subjected to a sham procedure involving an incision in the scrotal sac. Animals were evaluated weekly for body weight gain and naso-anal length growth. In adulthood, depressive-like behavior was assessed using the forced swim test. Glial fibrillary acidic protein (GFAP; assessed by immunohistochemistry), an astrocytic marker of neuroinflammation, was evaluated in the hypothalamus, striatum, and frontal cortex. Data normality was assessed using the Shapiro–Wilk or Kolmogorov–Smirnov tests. Parametric data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test, while nonparametric data were analyzed using the Kruskal–Wallis (KW) test followed by Dunn’s post hoc test. A significance level of 5% (p < 0.05) was adopted.

Results

The hypogonadism model reduced naso-anal growth (ANOVA: F(2, 18) = 43.11, p < 0.0001; CO vs. HG, p = 0.01), induced depressive-like behavior (immobility time, KW: 15.19, p < 0.0001; CO vs. HG, p = 0.05), and increased astrocytic expression in the frontal cortex (KW: 8.54, p = 0.0064; CO vs. HG, p = 0.01), without affecting body weight gain (ANOVA: F(2, 18) = 116.80, p < 0.0001; no difference between CO and HG). The hyperestrogenism model prevented body weight gain (CO vs. HE, p < 0.0001) and naso-anal growth (CO vs. HE, p < 0.0001), produced an antidepressant-like profile (no difference between CO and HE), and decreased astrocytic expression in the hypothalamus (ANOVA: F(2, 12) = 15.52, p = 0.0001; CO vs. HE, p < 0.01).

Conclusions

Pubertal hypogonadism impaired physical development and induced depressive-like behavior in rats, potentially involving neuroinflammatory processes in the frontal cortex. In contrast, hyperestrogenism further impaired physical development, produced an antidepressant-like effect, and was associated with reduced astrocytic expression in the hypothalamus. The hyperestrogenism model may represent a suitable approach for studying hormone therapy and feminization.

References

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