Sex hormones modulate brain damage in multiple sclerosis: MRI evidence

Tomassini, Valentina; Onesti, Emanuela; Mainero, Caterina; Giugni, Elisabetta; Paolillo, Andrea; Salvetti, M.; Nicoletti, Ferdinando; Pozzilli, Carlo

doi:10.1136/jnnp.2003.033324

Cited by 138 publications

(105 citation statements)

References 29 publications

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“…These studies suggest that androgens are more protective than estrogens in ameliorating EAE. The lowest levels of serum testosterone in women with MS correlate with the severity of the disease, another indication that androgens are protective (Tomassini et al, 2005). Our in vivo CNS studies also demonstrate that glia in the CNS is one axis affected by androgen withdrawal but also raises an intriguing possibility of a direct link between Olg and myelin degeneration and induction of an autoimmune response.…”

Section: Oligodendrocyte Proliferation and Cell Death Is Increased Inmentioning

confidence: 49%

Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents

et al. 2006

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Sexual dimorphism of neurons and astrocytes has been demonstrated in different centers of the brain, but sexual dimorphism of oligodendrocytes and myelin has not been examined. We show, using immunocytochemistry and in situ hybridization, that the density of oligodendrocytes in corpus callosum, fornix, and spinal cord is 20 -40% greater in males compared with females. These differences are present in young and aged rodents and are independent of strain and species. Proteolipid protein and carbonic anhydrase-II transcripts, measured by real-time PCR, are approximately two to three times greater in males. Myelin basic protein and 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase, measured by Western blots, are 20 -160% greater in males compared with females. Surprisingly, both generation of new glia and apoptosis of glia, including oligodendrocytes, are approximately two times greater in female corpus callosum. These results indicate that the lifespan of oligodendrocytes is shorter in females than in males. Castration of males produces a female phenotype characterized by fewer oligodendrocytes and increased generation of new glia. These findings indicate that exogenous androgens differentially affect the lifespan of male and female oligodendrocytes, and they can override the endogenous production of neurosteroids. The data imply that turnover of myelin is greater in females than in males. -Calpain, a protease upregulated in degeneration of myelin, is dramatically increased at both transcriptional and translational levels in females compared with males. These morphological, molecular, and biochemical data show surprisingly large differences in turnover of oligodendrocytes and myelin between sexes. We discuss the potential significance of these differences to multiple sclerosis, a sexually dimorphic disease, whose progression is altered by exogenous hormones.

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Section: Oligodendrocyte Proliferation and Cell Death Is Increased Inmentioning

confidence: 49%

Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents

et al. 2006

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“…Recently, the same group presented another study of gender-related modulation of pathological changes in RRMS where they related serum sex hormone levels to MRI characteristics of brain lesions in MS. In men, they reported a positive correlation between estradiol concentrations and brain damage as measured by both T1 and T2-lesion load (Tomassini et al, 2005). Greater brain damage, as documented by black holes, was associated with higher testosterone in women and higher estradiol levels in men, indicating that sex hormones (both estradiol and testosterone) are involved in the process leading to irreversible tissue damage, but that their role might differ between the sexes.…”

Section: Discussionmentioning

confidence: 95%

Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens

Moldovan

Cotleur

Zamor

et al. 2008

Journal of Neuroimmunology

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Multiple sclerosis affects more women than men. The reasons for this are unknown. Previously, we have shown significant differences in women versus men in inflammatory cytokine responses to the major protein component of myelin, proteolipid protein (PLP), which is thought to be a target in MS patients. Here, using the ELISPOT assay, we examined sex differences in single-cell secretion of Th1 and Th2 cytokines from freshly isolated PBMC between relapsing remitting (RR) MS patients and healthy individuals. Cells were stimulated with MS-associated antigens including proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and nondisease related antigens. Our data show a sex bias in the cytokine responses to multiple MS-relevant myelin antigens: Women with MS show IFNγ-skewed responses and men with MS show IL-5-skewed responses. These data extend our previous findings (Pelfrey et al., 2002): (1) by demonstrating gender skewing in cytokine responses to an expanded myelin antigen repertoire, which includes MBP, MOG and PLP; (2) by showing TNFα and IL-10 do not display comparable gender skewing compared to IFNγ and IL5; (3) by defining the patient population as early, untreated RR MS patients to avoid confounding factors, such as different disease stages/disability and immunomodulatory therapy; and (4) by showing HLA type does not appear to underlie the gender differences. These findings may explain increased susceptibility to MS in women and could contribute to the differences in disease severity between men and women.

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“…Another study has found a significantly higher number of Gd-enhanced lesions in women with abnormally low testosterone levels. In men, estradiol concentration has correlated with the volume of T1 lesions and the contrast-enhanced T2 lesions [138]. These data provide evidence that sex hormones modulate the development of brain tissue damages and repair in MS. Luchetti et al [139] have extended the research in gender differences of steroid synthesis and signaling in the brains of MS patients.…”

Section: Clinical Evidence For the Effects Of Sex Hormones On Diseasementioning

confidence: 53%

Sex Hormones and Multiple Sclerosis

Trenova¹

2016

Trending Topics in Multiple Sclerosis

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Experimental and clinical data about the influence of sex hormones on the course of multiple sclerosis (MS) grow rapidly during the past two decades. Estrogens, progesterone, and androgens have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in animals, and pregnancy in women is associated with a dramatic reduction in disease activity. Immunomodulatory and neuroprotective properties of sex hormones are the most probable underlying mechanisms, creating a background for testing similar hormonal treatments in humans. Several pilot studies in this field present promising results, but larger trials are necessary to identify the adverse events and to estimate precisely the place of sex steroids in multiple sclerosis therapeutic strategies.The objective of this chapter is to summarize the recent advances in the research about the effects of sex steroids in EAE and MS and to create a ground for the development of more powerful treatments in the future.

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Sex hormones modulate brain damage in multiple sclerosis: MRI evidence

Cited by 138 publications

References 29 publications

Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents

Proliferation and Death of Oligodendrocytes and Myelin Proteins Are Differentially Regulated in Male and Female Rodents

Multiple sclerosis patients show sexual dimorphism in cytokine responses to myelin antigens

Sex Hormones and Multiple Sclerosis

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