|
Sex-and age-related changes in epitestosterone
in relation to pregnenolone sulfate and testosterone in normal subjects.
Epitestosterone
has been demonstrated to act at various levels as a weak antiandrogen.
So far, its serum levels have been followed up only in males. Epitestosterone
and its major circulating precursor pregnenolone sulfate and T were
measured in serum from 211 healthy women and 386 men to find out whether
serum concentrations of epitestosterone are sufficient to exert its
antiandrogenic actions. In women, epitestosterone exhibited a maximum
around 20 yr of age, followed by a continuous decline up to menopause
and by a further increase in the postmenopause. In men, maximum epitestosterone
levels were detected at around 35 yr of age, followed by a continuous
decrease. Pregnenolone sulfate levels in women reached their maximum
at about age 32 yr and then declined continuously, and in males the
maximum was reached about 5 yr earlier and then remained nearly constant.
Epitestosterone correlated with pregnenolone sulfate only in males.
In both sexes a sharp decrease of the epitestosterone/T ratio around
puberty occurred. In conclusion, concentrations of epitestosterone
and pregnenolone sulfate are age dependent and, at least in prepubertal
boys and girls, epitestosterone reaches or even exceeds the concentrations
of T, thus supporting its role as an endogenous antiandrogen. The
dissimilarities in the course of epitestosterone levels through the
lifespan of men and women and its relation to pregnenolone sulfate
concentrations raise the question of the contribution of the adrenals
and gonads to the production of both steroids and even to the uniformity
of the mechanism of epitestosterone formation.
J Clin Endocrinol Metab . 2002 May;87(5):2225-31
Sex steroids and 5-en-3 beta-hydroxysteroids in specific regions
of the human brain and cranial nerves.
Sex steroids and 5-en-3 beta-hydroxysteroids were determined by radioimmunoassay
in specific regions of the human brain, in the anterior and posterior pituitary,
in one sensory organ, the retina and in the cranial nerves. Progesterone, androstenedione,
testosterone and estrone were found in all areas of the brain and in all the
cranial nerves but not in all cases. There was no sex difference except in
the case of androstenedione where values were higher in women in some brain
areas. Estrone values were always higher than those of estradiol in both men
and women. No 5 alpha-dihydrotestosterone was detected in any of the samples
studied. The values for pregnenolone, dehydroepiandrosterone and their sulfates
were much higher than those of the sex steroids in all areas of the brain and
in all the cranial nerves. Values for pregnenolone were greater than those
of its sulfate while those of dehydroepiandrosterone were in general equal
to or higher than those of its sulfate. The values for pregnenolone were greater
than those of dehydroepiandrosterone. There were no obvious regional differences
in the concentrations of the 5-en-3 beta-hydroxysteroids either in specific
areas of the brain or in the cranial nerves. But there was a definite trend
for the free dehydroepiandrosterone values to be higher in women. The possible
significance of these observations is discussed.
J Steroid Biochem . 1986 Sep;25(3):445-9
Individual differences in cognitive aging: implication of pregnenolone
sulfate.
In humans and animals, individual differences in aging of cognitive functions
are classically reported. Some old individuals exhibit performances similar
to those of young subjects while others are severely impaired. In senescent
animals, we have previously demonstrated a significant correlation between
the cognitive performance and the cerebral concentration of a neurosteroid,
the pregnenolone sulfate (PREG-S).Neurotransmitter systems modulated by this
neurosteroid were unknown until our recent report of an enhancement of acetylcholine
(ACh) release in basolateral amygdala, cortex and hippocampus induced by intracerebroventricular
(i.c.v.) or intracerebral administrations of PREG-S. Central ACh neurotransmission
is known to be involved in the regulation of memory processes and is affected
in normal aging and severely altered in human neurodegenerative pathologies
like Alzheimer's disease.In the central nervous system, ACh neurotransmission
is also involved in the modulation of sleep-wakefulness cycle, and particularly
the paradoxical sleep (PS). Relationships between paradoxical sleep and memory
are documented in the literature in old animals in which the spatial memory
performance positively correlates with the basal amounts of paradoxical sleep.
PREG-S infused at the level of ACh cell bodies (nucleus basalis magnocellularis,
NBM, or pedunculopontine nucleus, PPT) increases paradoxical sleep in young
animals.Finally, aging related cognitive dysfunctions, particularly those observed
in Alzheimer's disease, have also been related to alterations of mechanisms
underlying cerebral plasticity. Amongst these mechanisms, neurogenesis has
been extensively studied recently. Our data demonstrate that PREG-S central
infusions dramatically increase neurogenesis, this effect could be related
to the negative modulator properties of this steroid at the GABA(A) receptor
level.Taken together these data suggest that neurosteroids can influence cognitive
processes, particularly in senescent subjects, through a modulation of ACh
neurotransmission associated with paradoxical sleep modifications; furthermore,
our recent data suggest a critical role for neurosteroids in the modulation
of cerebral plasticity, mainly on hippocampal neurogenesis.
Prog Neurobiol . 2003 Sep;71(1):43-8
GABA--the quintessential neurotransmitter: electroneutrality,
fidelity, specificity, and a model for the ligand binding site of
GABAA receptors.
Alone of the known neurotransmitters, GABA is an electroneutral
zwitterion (pI = 7.3) at physiological pH. This confers the highest
probability of successfully traversing densely packed synaptic gaps
without interacting electrostatically with charged entities enroute,
making GABA a high fidelity neurotransmitter. Inhibitory tone in the
nervous system is coordinately coupled with physiological activity by
means of the GABA system, acidification increasing GABA formation and
its Cl- channel-opening efficacy, while decreasing its removal by transport
and metabolic degradation. The above, together with diminution upon
acidification of the postsynaptic efficacy of glutamate on excitatory
NMDA receptors constitutes a sensitively responsive mechanism by which
protons control levels of neural activity, locally and globally. A model
made of the GABA binding site of GABAA receptors based on H-bond and
hydrophobic interactions makes it seem unlikely that any other substance
known to occur in nerve tissue would give rise to a high noise level
at GABAA receptors.
Neurochem Res . 1993 Apr;18(4):365-76
The neurosteroid pregnenolone sulfate increases cortical acetylcholine
release: a microdialysis study in freely moving rats.
The effects of pregnenolone sulfate (Preg-S) administrations (0, 12, 48, 96,
and 192 nmol intracerebroventricularly) on acetylcholine (ACh) release in the
frontal cortex and dorsal striatum were investigated by on-line microdialysis
in freely moving rats. Following Preg-S administration, extracellular ACh levels
in the frontal cortex increased in a dose-dependent manner, whereas no change
was observed in the striatum. The highest doses (96 and 192 nmol) induced a
threefold increase above control values of ACh release, the intermediate dose
of 48 nmol led to a twofold increase, whereas after the dose of 12 nmol, the
levels of ACh were not different from those observed after vehicle injection.
The increase in cortical ACh reached a maximum 30 min after administration
for all the active doses. Taken together, these results suggest that Preg-S
interacts with the cortical cholinergic system, which may account, at least
in part, for the promnesic and/or antiamnesic properties of this neurosteroid.
J Neurochem . 1998 Nov;71(5):2018-22
Neurosteroids: deficient cognitive
performance in aged rats depends on low pregnenolone sulfate levels
in the hippocampus.
Pregnenolone
sulfate (PREG S) is synthesized in the nervous system and is a major
neurosteroid in the rat brain. Its concentrations were measured in
the hippocampus and other brain areas of single adult and aged (22-24
month-old) male Sprague-Dawley rats. Significantly lower levels were
found in aged rats, although the values were widely scattered and
reached, in about half the animals, the same range as those of young
ones. The spatial memory performances of aged rats were investigated
in two different spatial memory tasks, the Morris water maze and Y-maze.
Performances in both tests were significantly correlated and, accompanied
by appropriate controls, likely evaluated genuine memory function.
Importantly, individual hippocampal PREG S and distance to reach the
platform in the water maze were linked by a significant correlation,
i.e., those rats with lower memory deficit had the highest PREG S
levels, whereas no relationship was found with the PREG S content
in other brain areas (amygdala, prefrontal cortex, parietal cortex,
striatum). Moreover, the memory deficit of cognitively impaired aged
rats was transiently corrected after either intraperitoneal or bilateral
intrahippocampal injection of PREG S. PREG S is both a gamma-aminobutyric
acid antagonist and a positive allosteric modulator at the N-methyl-D-aspartate
receptor, and may reinforce neurotransmitter system(s) that decline
with age. Indeed, intracerebroventricular injection of PREG S was
shown to stimulate acetylcholine release in the adult rat hippocampus.
In conclusion, it is proposed that the hippocampal content of PREG
S plays a physiological role in preserving and/or enhancing cognitive
abilities in old animals, possibly via an interaction with central
cholinergic systems. Thus, neurosteroids should be further studied
in the context of prevention and/or treatment of age-related memory
disorders.
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14865-70
Role of pregnenolone, dehydroepiandrosterone and their sulfate
esters on learning and memory in cognitive aging.
Aging is a general process of functional decline which involves in particular
a decline of cognitive abilities. However, the severity of this decline differs
from one subject to another and inter-individual differences have been reported
in humans and animals. These differences are of great interest especially as
concerns investigation of the neurobiological factors involved in cognitive
aging. Intensive pharmacological studies suggest that neurosteroids, which
are steroids synthesized in the brain in an independent manner from peripheral
steroid sources, could be involved in learning and memory processes. This review
summarizes data in animals and humans in favor of a role of neurosteroids in
cognitive aging. Studies in animals demonstrated that the neurosteroids pregnenolone
(PREG) and dehydroepiandrosterone (DHEA), as sulfate derivatives (PREGS and
DHEAS, respectively), display memory-enhancing properties in aged rodents.
Moreover, it was recently shown that memory performance was correlated with
PREGS levels in the hippocampus of 24-month-old rats. Human studies, however,
have reported contradictory results. First, improvement of learning and memory
dysfunction was found after DHEA administration to individuals with low DHEAS
levels, but other studies failed to detect significant cognitive effects after
DHEA administration. Second, cognitive dysfunctions have been associated with
low DHEAS levels, high DHEAS levels, or high DHEA levels; while in other studies,
no relationship was found. As future research perspectives, we propose the
use of new methods of quantification of neurosteroids as a useful tool for
understanding their respective role in improving learning and memory impairments
associated with normal aging and/or with pathological aging, such as Alzheimer's
disease.
Brain Res Brain Res Rev . 2001 Nov;37(1-3):301-12
The neurosteroid pregnenolone sulfate infused into the medial
septum nucleus increases hippocampal acetylcholine and spatial memory
in rats.
The effects of an infusion of the neurosteroid pregnenolone sulfate into the
medial septum on acetylcholine release in the hippocampus and on spatial memory
were evaluated in two experiments. Results show that pregnenolone sulfate enhanced
acetylcholine release by more than 50% of baseline and improved recognition
memory of a familiar environment. Therefore, our results suggest that the septo-hippocampal
pathway could be involved in the promnesic properties of this neurosteroid.
Brain Res . 2002 Oct 4;951(2):237-42
Pregnenolone sulfate and aging of
cognitive functions: behavioral, neurochemical, and morphological
investigations.
Neurosteroids
are a subclass of steroids that can be synthesized in the central
nervous system independently of peripheral sources. Several neurosteroids
influence cognitive functions. Indeed, in senescent animals we have
previously demonstrated a significant correlation between the cerebral
concentration of pregnenolone sulfate (PREG-S) and cognitive performance.
Indeed, rats with memory impairments exhibited low PREG-S concentrations
compared to animals with correct memory performance. Furthermore,
these memory deficits can be reversed by intracerebral infusions of
PREG-S. Neurotransmitter systems modulated by this neurosteroid were
unknown until our recent report of an enhancement of acetylcholine
(ACh) release in basolateral amygdala, cortex, and hippocampus induced
by central administrations of PREG-S. Central ACh neurotransmission
is involved in the regulation of memory processes and is affected
in normal aging and in human neurodegenerative pathologies like Alzheimer's
disease. ACh neurotransmission is also involved in the modulation
of sleep-wakefulness cycle and relationships between paradoxical sleep
and memory are well documented in the literature. PREG-S infused at
the level of ACh cell bodies induces a dramatic increase of paradoxical
sleep in young animals. Cognitive dysfunctions, particularly those
observed in Alzheimer's disease, have also been related to alterations
of cerebral plasticity. Among these mechanisms, neurogenesis has been
recently studied. Preliminary data suggest that PREG-S central infusions
dramatically increase neurogenesis. Taken together these data suggest
that PREG-S can influence cognitive processes, particularly in senescent
subjects, through a modulation of ACh neurotransmission associated
with paradoxical sleep modifications; furthermore our recent data
suggest a role for neurosteroids in the modulation of hippocampal
neurogenesis.
Horm Behav . 2001 Sep;40(2):215-7
CSF neuroactive steroids in affective disorders: pregnenolone,
progesterone, and DBI.
Recently several steroid compounds have been discovered to act as neuromodulators
in diverse central nervous system (CNS) functions. We wondered if neuroactive
steroids might be involved in affective illness or in the mode of action of
mood-regulating medications such as carbamazepine. Levels of the neuroactive
steroids pregnenolone and progesterone, as well as the neuropeptide diazepam
binding inhibitor (DBI) (known to promote steroidogenesis), were analyzed from
cerebrospinal fluid (CSF) obtained by lumbar puncture (LP) from 27 medication-free
subjects with affective illness and 10 healthy volunteers. Mood-disordered
subjects who were clinically depressed at the time of the LP had lower CSF
pregnenolone (n = 9, 0.16 ng/ml) compared with euthymic volunteers (n = 10,
0.35 ng/ml; p < 0.01). In addition, pregnenolone was lower in all affectively
ill subjects (n = 26, 0.21 ng/ml), regardless of mood state on the LP day,
than healthy volunteers (p < 0.05). No differences were found for progesterone
or DBI levels by mood state or diagnosis. Progesterone, pregnenolone, and DBI
did not change significantly or consistently in affectively ill subjects after
treatment with carbamazepine. CSF pregnenolone is decreased in subjects with
affective illness, particularly during episodes of active depression. Further
research into the role of neuroactive steroids in mood regulation is warranted.
Biol Psychiatry . 1994 May 15;35(10):775-80
Low pregnenolone sulphate plasma concentrations in patients
with generalized social phobia.
BACKGROUND: Animal studies have shown that neuroactive steroids
modulate the activity of the gamma-aminobutyric acid type A/benzodiazepine
receptor complex and that these steroids display anxiolytic or anxiogenic
activity depending on their positive (e.g. allopregnanolone) or negative
allosteric modulation (e.g. dehydroepiandrosterone sulphate) of this
receptor. This study compared plasma levels of allopregnanolone, dehydroepiandrosterone
sulphate and pregnenolone sulphate in healthy controls and in patients
with generalized social phobia, as assessed with the Mini-International
Neuropsychiatric Interview. METHODS: Plasma concentrations of allopregnanolone,
pregnenolone sulphate, and dehydroepiandrosterone sulphate were measured
in 12 unmedicated male patients with generalized social phobia and 12
matched healthy male volunteers. RESULTS: Concentrations of pregnenolone
sulphate were significantly lower in patients with generalized social
phobia than in healthy controls. No statistically significant differences
were found for the concentrations of allopregnanolone and dehydroepiandrosterone
sulphate in plasma. CONCLUSIONS: These results are particularly interesting
since we also observed lower pregnenolone sulphate concentrations in
male patients suffering from generalized anxiety disorder. Their relevance
to the pathophysiology of social anxiety disorder remains to be determined.
Psychol Med . 2002 Jul;32(5):929-33
Key role for pregnenolone in combination therapy that promotes
recovery after spinal cord injury.
Controlled compressive injury to rat spinal cord was chosen
to test therapies that might attenuate the progression of tissue destruction
and locomotor deficits that characteristically occur after spinal injury.
A highly significant reduction of damage was achieved by immediate postinjury
treatment with a combination of the following: an antiinflammatory substance,
indomethacin; a stimulator of cytokine secretion, bacterial lipopolysaccharide;
and the parent steroid, from which all other steroids arise, pregnenolone.
This treatment reduced histopathological changes, spared tissue from
secondary injury, and increased restoration of motor function. Remarkably,
11 of 16 of the animals treated with the above combination were able
to stand and walk at 21 days after injury, 4 of them almost normally.
The results were far superior to those obtained in controls or in animals
to which the substances were given separately or in combination of two.
This approach may prove to be applicable to nervous system injury, in
general, and to injury in other tissues.
Proc Natl Acad Sci U S
A. 1994 Dec 6;91(25):12308-12 |