The sex-specific patterns of changes in hypothalamic-pituitary-gonadal axis during experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis develops during reproductive years in a sex-specific manner. Various neuroendocrine changes have been described in this inflammatory, demyelinating, and debilitating disease. We here aimed to determine the extent and sex specificity of alterations in the hypothalamic-pituitary-gonadal axis in the rat model of multiple sclerosis named experimental autoimmune encephalomyelitis (EAE). During the EAE course, the hypothalamic tissue showed transient upregulation of inflammatory marker genes Gfap, Cd68, Ccl2, and Il1b in both sexes, but accompanied by sex-specific downregulation of Kiss1 (in females only) and Gnrh1 (in males only) expression. In females, the expression of gonadotrope-specific genes Lhb, Cga, and Gnrhr was also inhibited, accompanied by decreased basal but not stimulated serum luteinizing hormone (LH) levels and a transient arrest of the estrous cycle. In contrast, Fshb expression and serum progesterone levels were transiently elevated, findings consistent with the maintenance of the corpora lutea, and elevated immunohistochemical labeling of ovarian StAR, a rate limiting protein in steroidogenic pathway. In males, downregulation of Gnrhr expression and basal and stimulated serum LH and testosterone levels were accompanied by inhibited testicular StAR protein expression. We propose that inflammation of hypothalamic tissue downregulates Kiss1 and Gnrh1 expression in females and males, respectively, leading to sexspecific changes downstream the axis.

The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators

“…A slight decrease was observed in Pomc expression during EAE, as was recently shown (Tanaka et al, 2020), suggesting that the observed weight loss in EAE may not be mediated by this anorectic peptide. Feeding behavior may thus rather be inhibited by proinflammatory cytokines, like IL-1β, and TNF-α (Sarraf et al, 1997;Milosevic et al, 2020). The status of the hypothalamus also implies that the observed increase in the pituitary Pomc expression, as well as the protein content of POMC and ACTH, may be associated to the high levels of proinflammatory cytokines, as previously suggested (Harbuz et al, 1992).…”

“…HPA hormones have a role in the maintenance of body homeostasis, regulation of the immune system, and neuroprotection, which emphasize the importance of adequate HPA response during EAE in order to help the system to overcome disease. Previously, we have shown that EAE induces inflammation in the hypothalamus (Milosevic et al, 2020), which can activate the HPA axis. This, however, does not seem to affect gene expression in the hypothalamus.…”

Is There an Association Between Multiple Sclerosis Epidemic and Socioeconomic Status in Iran? - A Descriptive-analytical Cross-sectional Study

“…These hormones gradually increase until the third trimester and subsequently decrease remarkably to relapse MS after the delivery (40,41). This fact was also proved in some animal studies so that the secretion of sex-related hormones could improve relapses and regulate the immune system signaling in many animals with experimental autoimmune encephalomyelitis (42,43). The MS reactivation after delivery may be owing to the breakdown of immunotolerance towards the fetus and the immunocompetence recovery (44).…”

Rat Ovarian Function Is Impaired during Experimental Autoimmune Encephalomyelitis

“…Experimental autoimmune encephalomyelitis was induced as previously described by a subcutaneous injection of encephalitogenic emulsion, prepared by mixing equal volumes of spinal cord homogenized in phosphate buffered saline (PBS, pH = 7.4) and complete Freund’s adjuvant [ 25 ]. The animals were examined daily and given grades based on the severity of EAE symptoms: 0—no symptoms, 1—tail atony, 2—unstable gait/hind limb weakness, 3—complete hind limb paralysis, 4—moribund state.…”

“…We have previously shown that, during acute EAE, the hypothalamic–pituitary–gonadal axis in rats of both sexes is disturbed [ 25 ] and testicular steroidogenic machinery components are downregulated [ 26 ]. Here, we show the presence of a higher number of large abnormal follicles in the ovaries at the peak of acute EAE.…”