Progesterone Synthesis in the Nervous System: Implications for Myelination and Myelin Repair

Abstract

Progesterone is well known as a female reproductive hormone and in particular for its role in uterine receptivity, implantation, and the maintenance of pregnancy. However, neuroendocrine research over the past decades has established that progesterone has multiple functions beyond reproduction. Within the nervous system, its neuromodulatory and neuroprotective effects are much studied. Although progesterone has been shown to also promote myelin repair, its influence and that of other steroids on myelination and remyelination is relatively neglected. Reasons for this are that hormonal influences are still not considered as a central problem by most myelin biologists, and that neuroendocrinologists are not sufficiently concerned with the importance of myelin in neuron functions and viability. The effects of progesterone in the nervous system involve a variety of signaling mechanisms. The identification of the classical intracellular progesterone receptors as therapeutic targets for myelin repair suggests new health benefits for synthetic progestins, specifically designed for contraceptive use and hormone replacement therapies. There are also major advantages to use natural progesterone in neuroprotective and myelin repair strategies, because progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins. The delivery of progesterone however represents a challenge because of its first-pass metabolism in digestive tract and liver. Recently, the intranasal route of progesterone administration has received attention for easy and efficient targeting of the brain. Progesterone in the brain is derived from the steroidogenic endocrine glands or from local synthesis by neural cells. Stimulating the formation of endogenous progesterone is currently explored as an alternative strategy for neuroprotection, axonal regeneration, and myelin repair.

Progesterone Reduces Secondary Damage, Preserves White Matter, and Improves Locomotor Outcome after Spinal Cord Contusion

“…[9][10][11][12][63][64][65][66][67] We have demonstrated in previous works that chronic PROG administration increases the expression of transcription factors that define oligodendrocyte linage, such as Olig2 and Nkx2.2 after spinal cord transection. 21,29 In the present work, we report that PROG treatment reduced the loss of oligodendrocyte numbers and MBP immunoreactivity produced by SCI.…”

“…7,8 Progesterone (PROG) could represent a good candidate for therapy, because it is neuroprotective, promyelinating, and antiinflammatory in pathologies of peripheral and central nervous systems. [9][10][11][12] Specifically, in experimental brain trauma, PROG reduces edema and inflammatory cytokines, prevents neuronal loss and mitochondrial dysfunction, and improves functional outcomes. [13][14][15] This has permitted the development of two Phase II clinical trials that have recently shown significant improvements in patients with traumatic brain injury receiving PROG.…”

Neuroactive steroids, their metabolites, and neuroinflammation

“…Moreover, as demonstrated in experimental models of several neurodegenerative disorders, the administration of neuroactive steroids is able to favor several protective/reparative processes like inhibition of neuronal death, promotion of neurogenesis, and myelination, as well as reduction of neuroinflammation (Brinton & Wang 2006, Garcia-Segura & Balthazart 2009, Melcangi et al 2011, Kipp et al 2012, Panzica et al 2012, Schumacher et al 2012. Intriguing is the modulation of this last process.…”

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve

“…19 Perhaps in the present experiments progesterone facilitated the release of trophic factors from nearby Schwann cells. 31,32,[45][46][47] Nerve sectioning plays a fundamental role in aberrant innervation, since it occurred even in animals implanted with silicone tubes. In our study, the synaptic connectivity between the nerve supply to the gastrocnemius muscle and the muscle itself seemed to be functional.…”