You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
reproductive aging even precedes the clinical manifestations of menopause or andropause and is a major determinant in sexual behavior and maintenance of optimal cognitive functions .
this neurodegenerative environment is characterized by neuronal loss , physical deterioration , loss of the blood - brain barrier and systemic inflammation .
the control of neuroendocrine changes ( devoto et al . , 2012 ) in the aging process may be crucial to maintain sexual behavior and improve brain function through neuroprotection or neurogenesis .
estrogen and its metabolites are important paracrine modulators of the function of hypophysis ( garca - barrado et al . , 2016 ) , corpus luteum ( henrquez et al . , 2016 ) and hippocampus ( farinetti et al . , 2015 ) , being determinant on ovarian and brain performance during aging process .
estrogen replacement therapy can decrease risk of memory disturbances in menopausal women ( rettberg et al .
indeed , brain synthesis of steroids is able to modulate several mechanisms related to neurogenesis , neural plasticity and memory functions .
peripheral steroid hormones also have important regulatory effects on cns . in animal models , ovarian cycle modulates abundance and location of neurotrophic factor in hippocampal neurons .
estradiol modulates neuroplasticity showing sex - specific differences in synaptogenesis in adult hippocampus ( brandt et al . , 2013 ) . in turn , the hippocampus is able to synthesize estrogens that are implied in learning processes and spatial and contextual memory .
either locally produced or exogenous steroids may provide neuroprotective and neuroregenerative effects . specifically , exogenous estradiol increases the formation of dendritic spines in hippocampus and medial prefrontal cortex of ovariectomized female mice ( tuscher et al . ,
these findings have added new information on use of estrogen receptor ligands for improving cognitive performance in postmenopausal women .
there is ample evidence indicating that estrogens and their metabolites are able to promote regeneration , plasticity and health of the nervous system , while its decrease or absence is associated with impaired physical and mental health besides increased risk of cardiovascular and neurodegenerative diseases ( bean et al . , 2015 ) .
the efficacy of estrogen therapy in neurodegenerative processes has nevertheless been controversial given the heterogeneity of clinical results besides some discrepancies between experimental and clinical studies .
for instance , hormone treatment has been reported to have beneficial effects on the risk of alzheimer 's disease in menopausal women , whereas other reports question its overall benefits .
these discrepancies may be due to genetic and hormonal differences , time at onset of neurodegenerative disorders and time at which hormone treatment is started , the type and possibly the scheduling of hormone treatment ( villa et al .
detrimental effects of hormone treatment on heart attack , stroke or deep vein thrombosis may be due to pro - thrombotic actions of estrogens in individuals with acute disruption of atherosclerotic plaques ( liu and yang , 2013 ) .
the main obstacle to study the effects and design suitable hormone therapies is the fact that estrogens do not seem to play a primary role as promoters of the neurodegenerative program but participate only in the complex combination of events that trigger neurodegeneration .
the success of estrogen therapies would thus depend on a careful consideration of not only the pathway being targeted by the treatment but also the sources of variability of effects , such as the nature of the disease process , or the amplification of effects mediated by modulators as trp ( transient receptor potential ) v1 channel .
the molecular identity of the estrogen - dependent pathway responsible to activate neuroprotection is unknown .
we propose that trp ion channel family , and specifically transient receptor potential cation channel , subfamily v , member 1 ( trpv1 ) , are able to act like ionotropic receptors of steroids offering a novel pharmacological target in neuroprotection and neuroregeneration . in this commentary
we focus on the trpv1 effects related to promotion of cell protection and self - repair , which could be particularly important in phenomena underlying neurodegenerative diseases and central nervous system repair , as well as in cell therapy development .
estrogens comprise a group of structurally related molecules among which 17-estradiol is the most predominant and active .
estrogens are cholesterol derived - molecules produced mainly by gonads , but also adrenal gland and hippocampus , which express the enzyme aromatase , are able to produce estrogens from androgens .
estrogens perform important physiological functions and exert pleiotropic effects in different cell types and organs including immune , bone , gastrointestinal , respiratory , reproductive , cardiovascular and nervous system . in brain , estrogens exert several effects as embryonic neurogenesis , excitatory synapse formation , neuroprotective and cognitive - enhancing effects and memory .
these effects are elicited by multiple pathways involving regulation of neurotransmitter release , increase in the number of dendritic spines , regulation of calcium homeostasis and improvement of mitochondrial function ( zhang et al . , 2016 ) .
classically , estrogens have been thought to exert their effects via a genomic mechanism involving binding of estrogen to nuclear receptors and subsequent regulation of specific gene transcription .
the genomic action typically takes several hours for the effect to be manifest due to either transcription and translation times of estrogen - regulated genes . in physiological conditions estrogens
the regulatory effects of estrogens have raised great interest due to evidence that estrogens may delay onset or reduce the severity of several neurological disorders , as well as ischemia - reperfusion brain damage ( siddiqui et al . , 2016 ) .
the effect of estrogens in cns could be related with two important functions : 1 ) promoting cell proliferation and differentiation and 2 ) neuroprotection against oxidative injuries .
recent data have highlighted the role of estrogens in neurogenic activity in mammals and other vertebrates .
ovariectomized female rats exhibit a decrease in neurogenesis in dentate gyrus , whichcan be reversed by 17-estradiol .
similar effects have been detected in the subventricular zone of the forebrain and the subgranular zone of the dentate gyrus of the hippocampus .
it has been reported that 17-estradiol increases the ratio of neurons toglia cells in neural stem cells in vitro and that it could modulate the differentiation of embryonic stem cells inducing neuronal phenotype ( murashov et al . , 2004 ) .
treatment with estradiol induces important effects on synapse formation such as increased neurite outgrowth and dendrite spine formation ( vierk et al . , 2014 ; gervais et al . , 2015 )
estradiol powerfully protects the brain against damage caused by mechanical or chemical injury by activating multiple mechanisms . the proposed cellular mechanisms to prevent cell death in models as stroke , deprivation , or oxidative environment , involve mitochondrial membrane potential improvement , prevention of atp decay and reduction of ros generation , via increased expression of anti - apoptotic proteins like bcl-2 and inhibition of pro - apoptotic proteins like bim and bad .
aromatase knock - out adult female rats exhibit exaggerated spontaneous apoptosis in neurons of the frontal cortex compared to wild type animals strengthening the anti - apoptotic role of estrogens .
a large body of evidence has currently emerged showing rapid effects of high - concentration estrogens that appear to involve membrane - associated signaling complexes capable of responding within seconds or minutes .
the kinetics of such responses are inconsistent with a mechanism requiring gene transcription and may be independent of estrogen receptors .
for instance , 17-estradiol conjugated to bsa has been shown to be an impermeable plasma membrane compound and has been used to study the role of membrane er in producing the non - genomic effects of estradiol .
these rapid non - genomic actions of estrogens involve mainly modulation of ion channels conduction and permeation and transient increase of intracellular ca , which are related with signaling pathways that are critical for plasticity , cognition , neuroprotection and neurogenesis .
the diversity of estrogens mechanisms of action amplifies the regulatory possibilities of cellular stress response and regeneration .
it is likely that estrogens are able to induce both cell responses , non - genomic and genomic , controlling cellular reactions to acute stress that are critical to maintain the viability and long - term effects that promote cell survival and regeneration .
yet , the still unclear mechanisms of rapid action of estrogens are possibly key to understand how estrogens exert their purported beneficial effects .
steroids exert pleiotropic functions not only through nuclear receptor , but also via a direct interaction with membrane receptors .
17-estradiol binds to the  subunit of the maxi - k potassium channel and activates it in vascular smooth muscle and in neuron - derived cell line , 17-estradiol also binds directly to  subunit of l - type calcium channel enhancing their activity .
the polymodal transient receptor potential ion channels ( trp ) family comprises a broad variety of non - selective cationic channels that are able to integrate multiple physicochemical stimuli including voltage , temperature , osmolality and several hydrophobic ligands such a vanilloids and phospholipids ( diaz - franulic et al . , 2016 ) have been proposed as potential targets of steroids ( nilius and voets , 2008 ) . regarding trpv activity ,
besides these rapid effects , 17-estradiol increases the expression of trpv1 in uterine cervical afferent neurons as well as in dorsal root ganglion cells through mechanisms that are dependent on er and er , suggesting reproductive cycle control of nociception in primary afferent neurons ( cho and chaban , 2012 ) .
it seems that different molecules could work cooperatively in channel activation , and some of them like pip2 , cholesterol or capsaicin bind to a promiscuous hydrophobic pocket within the channel ( gao et al . , 2016 ) .
while almost all steroids tested in trpv1 inhibit capsaicin - induced currents in rat dorsal root ganglion neurons , few reports indicate that only 17-estradiol could enhance these currents and the expression of the channel at least in dorsal root ganglion neurons , and little is known about direct trpv1 modulation by estrogens . since estrogens have been involved in neural protection and regeneration in several organs and predominantly in the brain , understanding their role on trpv1 activity is of particular interest to characterize these processes .
several data suggest that estrogen metabolites and precursors like cholesterol and testosterone can inhibit trpv1 activity .
it is likely that estrogens and its precursors occupy competitively the same hydrophobic pocket but only the aromatic steroid 17-estradiol is able to activate the channel , what could partly explain its neurogenic or neuroprotective functions . under this hypothesis
, 17-estradiol might enhance endogenous neuroprotective mechanisms and foster favorable environment to stem cells grafts survival .
the control of this mechanism could generate molecular strategies to decrease oxidative stress - induced neural progenitor death ( ramirez - barrantes et al . , 2016 )
molecular , cellular and tissue hypotheses integration for multilevel mechanisms of action to be tested in clinical trials .
physiological and pharmacological relationships at different levels of complexity lead into neuroprotective effects that are clinically relevant .
trpv1 channel offers a novel pharmacological target that may modulate the actions of estrogens with significant implications on clinical efficacy .
er : estrogen receptor ; trpv1 : transient receptor potential cation channel , subfamily v , member 1 .
certainly , stem cell transplantation is the most promising technique for the treatment of nervous system damage . specifically
, regenerative perspective should include the cellular fate of damaged cells or implanted cells through steroid - dependent stimulation ( labombarda and garcia - ovejero , 2014 ) , growth factors , cytokines and neurotransmitters ( singh et al .
although the beneficial effects of stem cell transplantation in experimental models have been widely documented , the development of a massive technology depends on the application and reproducibility of results in clinical environment .
a neurodegenerative environment induces neuronal loss , physical deterioration , loss of the blood brain barrier and systemic inflammation .
there is ample evidence supporting promotion of regeneration , plasticity and health of the nervous system by steroids and their metabolites ( labombarda and garcia - ovejero , 2014 ) , while its diminution or absence is associated with impaired physical and mental health and increased risk of cardiovascular disease and neurodegenerative diseases .
the effectiveness of a pro - regenerative therapeutic agent for systemic use can be tested in clinical trials .
menopause constitutes a relevant model of estrogens production decline associated with progressive cognitive impairment related to ageing ( rettberg et al . , 2016a ) , which allows exploring the role of trpv1 as a mediator of the therapeutic effects of exogenous steroids .
exploring these hypotheses in the clinical arena may help proposing personalized strategies of hormone replacement therapy focused on sexual and cognitive health .
aging induces physical deterioration , loss of the blood brain barrier , neuronal loss - induced mental and neurodegenerative diseases . 
 hypotalamus - hypophysis - gonad axis aging precedes symptoms of menopause or andropause and is a major determinant of sensory and cognitive integrated function . 
 sexual steroids support important functions , exert pleiotropic effects in different sensory cells , promote regeneration , plasticity and health of the nervous system . 
 their diminution is associated with impaired cognitive and mental health and increased risk of neurodegenerative diseases . 
 then , restoring neuroendocrine axes during aging can be key to enhance brain health through neuroprotection and neuroregeneration , depending on the modulation of plasticity mechanisms . estrogen - dependent transient receptor potential cation channel , subfamily v , member 1 ( trpv1 ) expression induces neuroprotection , neurogenesis and regeneration on damaged tissues 
 . agonists of trpv1 can modulate neuroprotection and repair of sensitive neurons , while modulators as other cognitive enhancers may improve the survival rate , differentiation and integration of neural stem cell progenitors in functional neural network . 
 menopause constitutes a relevant clinical model of steroidal production decline associated with progressive cognitive and mental impairment , which allows exploring the effects of hormone therapy in health outcomes such as dysfunction of cns . 
 simulating the administration of hormone therapy to virtual menopausal individuals allows assessing its hypothetical impact and sensitivity to conditions that modify the effectiveness and efficiency .