Roles of Progesterone, Testosterone and Their Nuclear Receptors in Central Nervous System Myelination and Remyelination

Abstract

Progesterone and testosterone, beyond their roles as sex hormones, are neuroactive steroids, playing crucial regulatory functions within the nervous system. Among these, neuroprotection and myelin regeneration are important ones. The present review aims to discuss the stimulatory effects of progesterone and testosterone on the process of myelination and remyelination. These effects have been demonstrated in vitro (i.e., organotypic cultures) and in vivo (cuprizone- or lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE)). Both steroids stimulate myelin formation and regeneration by acting through their respective intracellular receptors: progesterone receptors (PR) and androgen receptors (AR). Activation of these receptors results in multiple events involving direct transcription and translation, regulating general homeostasis, cell proliferation, differentiation, growth and myelination. It also ameliorates immune response as seen in the EAE model, resulting in a significant decrease in inflammation leading to a fast recovery. Although natural progesterone and testosterone have a therapeutic potential, their synthetic derivatives—the 19-norprogesterone (nestorone) and 7α-methyl-nortestosterone (MENT), already used as hormonal contraception or in postmenopausal hormone replacement therapies, may offer enhanced benefits for myelin repair. We summarize here a recent advancement in the field of myelin biology, to treat demyelinating disorders using the natural as well as synthetic analogs of progesterone and testosterone.

Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan

“…Sex hormones, including estrogens, progestogens, and androgens, all modulate oligodendrogenesis and myelogenesis [ 31 , 205 ]. Interestingly, males and females display regional differences in white matter density [ 206 , 207 ].…”

Uncovering sex differences of rodent microglia

“…Multiple lines of evidence point to dysfunctional glial and neuronal functions as one possible factor that explains sex differences in CNS disease [16]. Sex steroid hormone exposure during critical periods may also exert crucial effects on the functions of several immune cell types [17,18]. In an attempt to understand such sex differences of microglia, the critical question is when and how microglia become different between males and females?…”

Hormonal Regulation of Oligodendrogenesis II: Implications for Myelin Repair

“…Sex hormones, including the estrogens, progestogens, and androgens, all modulate oligodendrogenesis and myelogenesis, as we describe in our companion review [ 33 , 73 , 74 ]. Indeed, males and females are differentially affected by demyelinating disorders such as MS [ 11 ], and differences in sex hormones might account for some of this sex-specific risk ( Figure 2 ).…”

“…Progesterone has a significant impact on remyelination (for a recent review, see Reference [ 73 ]). Progesterone’s ability to repair myelin in the adult CNS extends across multiple injury models, including SCI, LPC or cuprizone-induced demyelination, and EAE.…”