Effect of Caffeine on the Inflammatory-Dependent Changes in the GnRH/LH Secretion in a Female Sheep Model

Abstract

Caffeine is one of the most widely consumed psychoactive drugs in the world. It easily crosses the blood-brain barrier, and caffeine-interacting adenosine and ryanodine receptors are distributed in various areas of the brain, including the hypothalamus and pituitary. Caffeine intake may have an impact on reproductive and immune function. Therefore, in the present study performed on the ewe model, we decided to investigate the effect of peripheral administration of caffeine (30 mg/kg) on the secretory activity of the hypothalamic-pituitary unit which regulates the reproductive function in females during both a physiological state and an immune/inflammatory challenge induced by lipopolysaccharide (LPS; 400 ng/kg) injection. It was found that caffeine stimulated (p < 0.01) the biosynthesis of gonadotropin-releasing hormone (GnRH) in the hypothalamus of ewe under both physiological and inflammatory conditions. Caffeine also increased (p < 0.05) luteinizing hormone (LH) secretion in ewes in a physiological state; however, a single administration of caffeine failed to completely release the LH secretion from the inhibitory influence of inflammation. This could result from the decreased expression of GnRHR in the pituitary and it may also be associated with the changes in the concentration of neurotransmitters in the median eminence (ME) where GnRH neuron terminals are located. Caffeine and LPS increased (p < 0.05) dopamine in the ME which may explain the inhibition of GnRH release. Caffeine treatment also increased (p < 0.01) cortisol release, and this stimulatory effect was particularly evident in sheep under immunological stress. Our studies suggest that caffeine affects the secretory activity of the hypothalamic-pituitary unit, although its effect appears to be partially dependent on the animal's immune status.

Keywords: GnRH; caffeine; hypothalamus; inflammation; luteinizing hormone; pituitary.

Figure 1

Effect of lipopolysaccharide (LPS; 400 ng/kg; iv.) and caffeine (30 mg/kg; iv.) injections on the concentration of luteinizing hormone (LH) (a) and follicle-stimulating hormone (FSH) (b) in the blood plasma. The data are presented as the mean value ± S.E.M. (n = 6 animals per group) of hormone concentration assayed during a period after the treatment (2 to 3 h after). Significant differences marked with different capital letters were analyzed by a two-way ANOVA followed by a Fisher’s post hoc test. Statistical significance was stated when p < 0.05.

Figure 2

Effect of lipopolysaccharide (LPS; 400 ng/kg; iv.) and caffeine (30 mg/kg; iv.) injections on the concentration of cortisol in the blood plasma. The data are presented as the mean value ± S.E.M. (n = 6 animals per group) of hormone concentration assayed during a period after the treatment (2 to 3 h after). Significant differences marked with different capital letters were analyzed by a two-way ANOVA followed by a Fisher’s post hoc test. Statistical significance was stated when p < 0.05.

Figure 3

Effect of lipopolysaccharide (LPS; 400 ng/kg; iv.) and caffeine (30 mg/kg; iv.) injections on the concentration of estradiol (E2) in the blood plasma. The data are presented as the mean value ± S.E.M. (n = 6 animals per group) of hormone concentration assayed during a period after the treatment (2 to 3 h after). Significant differences marked with different capital letters were analyzed by a two-way ANOVA followed by a Fisher’s post hoc test. Statistical significance was stated when p < 0.05.

Figure 4

Effect of lipopolysaccharide (LPS; 400 ng/kg; iv.) and caffeine (30 mg/kg; iv.) injections on the concentration of gonadotropin-releasing hormone (GnRH) in the preoptic area of the hypothalamus. The data are presented as the mean value ± S.E.M. (n = 6 animals per group). Significant differences marked with different capital letters were analyzed by a two-way ANOVA followed by a Fisher’s post hoc test. Statistical significance was stated when p < 0.05.