Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

Abstract

Progesterone has a broad spectrum of actions in the brain. Among these, the neuroprotective effects are well documented. Progesterone neural effects are mediated by multiple signaling pathways involving binding to specific receptors (intracellular progesterone receptors (PR); membrane-associated progesterone receptor membrane component 1 (PGRMC1); and membrane progesterone receptors (mPRs)) and local bioconversion to 3α,5α-tetrahydroprogesterone (3α,5α-THPROG), which modulates GABAA receptors. This brief review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain. First, we succinctly describe the biosynthetic pathways and the expression of enzymes and receptors of progesterone; as well as the changes observed after brain injuries and in neurological diseases. Then, we summarize current data on the differential fluctuations in brain levels of progesterone and its neuroactive metabolites according to sex, age, and neuropathological conditions. The third part is devoted to the neuroprotective effects of progesterone and 3α,5α-THPROG in different experimental models, with a focus on traumatic brain injury and stroke. Finally, we highlight the key role of the classical progesterone receptors (PR) in mediating the neuroprotective effects of progesterone after stroke.

From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy

“…3α,5α-THPROG, a metabolite of progesterone, showed superior effects on pathophysiology, cognition, and memory in a 3xTg AD mouse model [177,178], and the underlying mechanism involved 3α,5α-THPROG regulating glucose metabolism, mitochondrial bioenergetics, and cholesterol homeostasis in the brain [179]. In contrast to the inconclusive results of progesterone treatment for PD [58], 3α,5α-THPROG showed better improved cognitive and motor functions in MPTPor 6-OHDA-induced PD mouse models [180,181].…”

“…Circulating progesterone is decreased during menopausal transition and drops dramatically following menopause [56,57]. The neuroprotective effects of progesterone are well documented, and progesterone and its metabolites, 5α-dihydroprogesterone (5α-DHPROG) and 3α,5αtetrahydroprogesterone (3α,5α-THPROG), decrease with aging [58]. Levels of insulin-like growth factor 1 (IGF-1), which can be regulated by estrogen, are also reported to decline in serum with aging, especially after the age of 40 years [59,60].…”

Phytoprogestins: Unexplored Food Compounds with Potential Preventive and Therapeutic Effects in Female Diseases

“…In addition, progesterone plays an essential role in the physiology of non-reproductive tissues, such as the cardiovascular system, the central nervous system, and bone tissue. In the brain, progesterone is neuroprotective, and its metabolite allopregnanolone is a GABAergic agonist [12,13] (Figure 1).…”

Sex differences in recovery of motor function in a rhesus monkey model of cortical injury

“…Estradiol acts on ER-α and ER-β receptors expressed on neurons, astrocytes, and microglia to modulate the inflammatory response and promote repair cascades in rodents [ 13 , 16 , 17 , 19 , 24 , 25 ]. Progesterone has also been attributed to neuroprotection in animal models of brain damage [ 26 – 28 ]. For example, administration of progesterone to ovariectomized female and male rodents resulted in reduced infarct volume and improved functional recovery after MCAO [ 29 – 34 ].…”

“…Despite considerable evidence of the effect of estradiol and progesterone on recovery and inflammation following cortical injury [ 15 – 19 , 26 , 36 , 41 – 46 ], there have been limited studies looking at cortical injury and recovery in the female brain in a higher order, gyrencephalic animal species. Further, while epidemiological studies in humans have shed light on sex differences in the clinical risk and severity of stroke, variability in the human datasets precludes precise quantitative studies and establishment of predictive models of how sex affects severity of functional impairments and degree of recovery after injury.…”