JAN AUSHADHI KOTTIYAM
Used to treat male Hypogonadizam
Other nuclear receptors
DHEA does not bind to or activate the progesterone, glucocorticoid, or mineralocorticoid receptors.Other nuclear receptor targets of DHEA besides the androgen and estrogen receptors include the PPARα, PXR, and CAR. However, whereas DHEA is a ligand of the PPARα and PXR in rodents, it is not in humans. In addition to direct interactions, DHEA is thought to regulate a handful of other proteins via indirect, genomic mechanisms, including the enzymes CYP2C11 and 11β-HSD1 – the latter of which is essential for the biosynthesis of the glucocorticoids such as cortisol and has been suggested to be involved in the antiglucocorticoid effects of DHEA – and the carrier protein IGFBP1.
DHEA has been found to directly act on several neurotransmitter receptors, including acting as a positive allosteric modulator of the NMDA receptor, as a negative allosteric modulator of the GABAA receptor, and as an agonist of the σ1 receptor.
Neurotrophin receptors
In 2011, the surprising discovery was made that DHEA, as well as DHEA-S, directly bind to and activate the TrkA and p75NTR, receptors of neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), with high affinity. DHEA was subsequently also found to bind to the TrkB and TrkC with high affinity, though it notably activated the TrkC but not the TrkB. DHEA and DHEA-S bound to these receptors with affinities that were in the low nanomolar range (around 5 nM), although the affinities were nonetheless approximately two orders of magnitude lower relative to highly potent polypeptide neurotrophins like NGF (0.01–0.1 nM). In any case, DHEA and DHEA-S both circulate at requisite concentrations to activate these receptors and were thus identified as important endogenous neurotrophic factors. They have since been labeled "steroidal microneurotrophins", due to their small-molecule and steroidal nature relative to their polypeptide neurotrophin counterparts.Subsequent research has suggested that DHEA and/or DHEA-S may in fact be phylogenetically ancient "ancestral" ligands of the neurotrophin receptors from early on in the evolution of the nervous system. The findings that DHEA binds to and potently activates neurotrophin receptors may explain the positive association between decreased circulating DHEA levels with age and age-related neurodegenerative diseases.
Microtubule-associated protein 2
Similarly to pregnenolone, its synthetic derivative 3β-methoxypregnenolone (MAP-4343), and progesterone, DHEA has been found to bind to microtubule-associated protein 2 (MAP2), specifically the MAP2C subtype (Kd = 27 µM). However, it is unclear whether DHEA increases binding of MAP2 to tubulin like pregnenolone.
Used to treat male Hypogonadizam
Dehydroepiandrosterone (DHEA), also known as androstenolone,
is an endogenous steroid hormone. It is one of the most abundant circulating
steroids in humans, in whom it is produced in the adrenal glands,the gonads,
and the brain, where it functions as a metabolic intermediate in the
biosynthesis of the androgen and estrogen sex steroids. However, DHEA also has a
variety of potential biological effects in its own right, binding to an array
of nuclear and cell surface receptors, and acting as a neurosteroid and
neurotrophin.
FUNCTIONS
As an androgen
DHEA and other adrenal androgens such as androstenedione,
although relatively weak androgens, are responsible for the androgenic effects
of adrenarche, such as early pubic and axillary hair growth, adult-type body
odor, increased oiliness of hair and skin, and mild acne. Women with complete
androgen insensitivity syndrome (CAIS), who have a non-functional androgen
receptor (AR) and are immune to the androgenic effects of DHEA and other
androgens, have absent or only sparse/scanty pubic and axillary hair and body
hair in general, demonstrating the role of DHEA, testosterone, and other
androgens in body hair development at both adrenarche and pubarche.
As a neurosteroid
As a neurosteroid and neurotrophin, DHEA has important effects
in the central nervous system.
BIOLOGICAL ACTIVITY
Hormonal activity
Androgen receptor
Although it functions as an endogenous precursor to more
potent androgens such as testosterone and DHT, DHEA has been found to possess
some degree of androgenic activity in its own right, acting as a low affinity
(Ki = 1 μM), weak partial agonist of the androgen receptor (AR). However, its
intrinsic activity at the receptor is quite weak, and on account of that, due
to competition for binding with full agonists like testosterone, it can actually
behave more like an antagonist depending on circulating testosterone and
dihydrotestosterone (DHT) levels, and hence, like an antiandrogen. However, its
affinity for the receptor is very low, and for that reason, is unlikely to be
of much significance under normal circumstances.
Estrogen receptors
In addition to its affinity for the androgen receptor, DHEA
has also been found to bind to and activate the ERα and ERβ estrogen receptors
with Ki values of 1.1 μM and 0.5 μM, respectively, and EC50 values of >1 μM
and 200 nM, respectively. Though it was found to be a partial agonist of the
ERα with a maximal efficacy of 30–70%, the concentrations required for this
degree of activation make it unlikely that the activity of DHEA at this
receptor is physiologically meaningful. Remarkably however, DHEA acts as a full
agonist of the ERβ with a maximal response similar to or actually slightly
greater than that of estradiol, and its levels in circulation and local tissues
in the human body are high enough to activate the receptor to the same degree
as that seen with circulating estradiol levels at somewhat higher than their
maximal, non-ovulatory concentrations; indeed, when combined with estradiol
with both at levels equivalent to those of their physiological concentrations,
overall activation of the ERβ was doubled. As such, it has been proposed that
DHEA may be an important and potentially major endogenous estrogen in the body.
Other nuclear receptors
DHEA does not bind to or activate the progesterone, glucocorticoid, or mineralocorticoid receptors.Other nuclear receptor targets of DHEA besides the androgen and estrogen receptors include the PPARα, PXR, and CAR. However, whereas DHEA is a ligand of the PPARα and PXR in rodents, it is not in humans. In addition to direct interactions, DHEA is thought to regulate a handful of other proteins via indirect, genomic mechanisms, including the enzymes CYP2C11 and 11β-HSD1 – the latter of which is essential for the biosynthesis of the glucocorticoids such as cortisol and has been suggested to be involved in the antiglucocorticoid effects of DHEA – and the carrier protein IGFBP1.
Neurosteroid activity
Neurotransmitter receptorsDHEA has been found to directly act on several neurotransmitter receptors, including acting as a positive allosteric modulator of the NMDA receptor, as a negative allosteric modulator of the GABAA receptor, and as an agonist of the σ1 receptor.
Neurotrophin receptors
In 2011, the surprising discovery was made that DHEA, as well as DHEA-S, directly bind to and activate the TrkA and p75NTR, receptors of neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), with high affinity. DHEA was subsequently also found to bind to the TrkB and TrkC with high affinity, though it notably activated the TrkC but not the TrkB. DHEA and DHEA-S bound to these receptors with affinities that were in the low nanomolar range (around 5 nM), although the affinities were nonetheless approximately two orders of magnitude lower relative to highly potent polypeptide neurotrophins like NGF (0.01–0.1 nM). In any case, DHEA and DHEA-S both circulate at requisite concentrations to activate these receptors and were thus identified as important endogenous neurotrophic factors. They have since been labeled "steroidal microneurotrophins", due to their small-molecule and steroidal nature relative to their polypeptide neurotrophin counterparts.Subsequent research has suggested that DHEA and/or DHEA-S may in fact be phylogenetically ancient "ancestral" ligands of the neurotrophin receptors from early on in the evolution of the nervous system. The findings that DHEA binds to and potently activates neurotrophin receptors may explain the positive association between decreased circulating DHEA levels with age and age-related neurodegenerative diseases.
Microtubule-associated protein 2
Similarly to pregnenolone, its synthetic derivative 3β-methoxypregnenolone (MAP-4343), and progesterone, DHEA has been found to bind to microtubule-associated protein 2 (MAP2), specifically the MAP2C subtype (Kd = 27 µM). However, it is unclear whether DHEA increases binding of MAP2 to tubulin like pregnenolone.
No comments:
Post a Comment