Dehydroepiandrosterone and Its Metabolite 5-Androstenediol: New Therapeutic Targets and Possibilities for Clinical Application
Abstract
:1. Introduction
2. Biosynthesis and Transformation of DHEA
3. DHEA and 5-AED Targets
3.1. Nuclear Receptors of Androstenes
3.2. Plasma Membrane Receptors of Androstenes
4. DHEA and 5-AED in ATC Classification
5. Current Clinical Use of DHEA and 5-AED
5.1. DHEA Vaginal Gel
5.2. Oral DHEA
6. Prospects and New Clinical Applications of DHEA and AED
6.1. Androstenes for Treatment of Mucosal Atrophy
6.2. Skin Anti-Aging Effect of Androstenes
6.3. The Effect of Androstenes on the Musculoskeletal System
6.4. The Use of Androstenes as Antitumor Agents
6.5. Radioprotective Effect of Androstenes
6.6. Immunostimulatory Action of Androstenes
6.7. Androstenes as Neuroprotectors
- -
- Inhibition of NMDA-induced NOS activity (10 µM);
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- Inhibition of Ca2+ influx into the mitochondrial matrix (100 µM);
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- Inhibition of mitochondrial respiration by acting on complex I of the respiratory chain (100 µM);
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- Inhibition of NF-κB activation (10–100 µM);
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- Inhibition of H2O2 and 4-hydroxynonenal (HNE) production;
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- Stimulation of SOD, GSH, GSH-peroxidase, and catalase;
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- Inhibition of lipid oxidation stimulated by H2O2/FeSO4;
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- A decrease in the serum concentration of TNFα and IL-6 (0.1–100 µM, maximal at 100 µM);
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- Antagonism to the negative effects of corticosterone on neurogenesis;
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- Increasing the proliferation of granule cells in the dentate gyrus;
- -
- Increasing the number of neural stem cells
- -
- Decreasing apoptosis;
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- Reducing NMDA-induced neurotoxicity (10 µM).
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbrevations
11OHA4 | 11β-Hydroxyandrostenedione |
5-AED | 5-androstene-3β,17β-diol |
A4 | Androstendione |
AKR1C3 | aldo-keto reductase family 1 member C3 |
Akt | protein kinase B |
APMK | 5′ adenosine monophosphate-activated protein kinase |
AR | androgen receptor |
ARS | acute radiation syndrome |
ATC | anatomical therapeutic chemical (classification) |
BBB | blood–brain barrier |
BMD | bone mineral density |
CAR | constitutive androstane receptor |
CT | clinical trials |
CSFs | colony-stimulating factors |
DHEA | dehydroepiandrosterone |
DHEA-S | dehydroepiandrosterone sulfate |
DHT | dihydrotestosterone |
E2 | 17β-estradiol |
EGF | epidermal growth factor |
ER | estrogen receptor |
hMSCs | human bone marrow-derived mesenchymal stem cells |
HSD3B2 | 3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase type II |
FSH | follicle-stimulating hormone |
G6PD | glucose-6-phosphate dehydrogenase |
GABA(A)R | gamma aminobutyric acid receptor type A |
G-CSF | granulocyte colony-stimulating factor |
GLUT2, 4 | glucose transporters member 2, 4 |
GPCRs | G protein-coupled receptors |
GPER | G protein-coupled estrogen receptor |
GPx | glutathione peroxidase |
GR | glucocorticoid receptor |
GSH | glutathione |
GSK-3β | glycogen synthase kinase-3 beta |
IGF-1 | insulin-like growth factor 1 |
IL-1, 6 | interleukins 1, 6 |
IRS-1 | insulin receptor substrate 1 |
IVF | in vitro fertilization |
HMGB1 | high mobility group box 1 |
HRT | hormone replacement therapy |
LH | luteinizing hormone |
LIF | leukemia inhibitory factor |
LXR | liver X receptor |
MDA | malondialdehyde |
MAPK | mitogen-activated protein kinase |
mAR | membrane androgen receptor |
MMP-1 | matrix metalloproteinase-1 |
mPR | membrane progesterone receptor |
NADP | nicotinamide adenine dinucleotide phosphate |
NF-kB | nuclear factor kappa B |
NGF | nerve growth factor |
NMDA | N-methyl-d-aspartate |
NOS | nitric oxide synthase |
NRF1 | nuclear respiratory factor 1 |
P75NTR | neurotrophin receptor p75 |
PGC-1α | peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PGRMC1,2 | progesterone receptor membrane component-1,2 |
PI3K | phosphatidylinositol 3-kinase |
POR | poor ovarian reserve |
PPAR | peroxisome proliferator-activated receptor |
PXR | pregnane X receptor |
ROS | reactive oxygen species |
S1R | sigma-1 receptor |
SLE | systemic lupus erythematosus |
SOD | superoxide dismutase |
T | testosterone |
TGFβ1 | transforming growth factor beta 1 |
TH1,2 | T-helper 1,2 |
TIMP-1 | tissue inhibitor of metalloproteinase-1 |
TLR4 | toll-like receptor 4 |
Tregs | T regulatory cells |
TRK | tropomyosin receptor kinase |
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Target | Action | Organism | Reference |
---|---|---|---|
Estrogen receptor alpha (ERα) | Binder (modulator) | Rat | [33] |
Estrogen receptor alpha (ERα) | Binder (modulator) | Human | [16] |
Estrogen receptor beta (ERβ) | Activator | Humans | [34] |
G protein-coupled estrogen receptor (GPER) | Activator | Humans | [35] |
γ-aminobutyric-acid-type A receptor (GABA (A)) | Antagonist | Humans | [36,37] |
N-methyl-d-aspartate (NMDA) receptor | Agonist | Humans | [37] |
N-methyl-d-aspartate (NMDA) receptor | Agonist | Rat | [38] |
Androgen receptor (AR) | Agonist | Humans | [39,40] |
Peroxisome proliferator-activated receptor alpha (PPARα) | Activator | Humans | [34,41] |
Sigma non-opioid intracellular receptor 1 | Agonist | Humans | [42] |
Nuclear receptor subfamily 1 group 1 member 2 (Pregnane X receptor) | Activator | Humans | [43] |
Nuclear receptor subfamily 1 group 1 member 2 (Constitutive andronstane receptor (CAR) | Activator | Humans | [44] |
GSK-3β glycogen-synthase-kinase-3β (GSK-3β) | Activator | Humans | [45] |
Glucose-6-phosphate dehydrogenase (G6PD) | Inhibitor | Humans | [46] |
Name of Steroid | AR | ERα | ERβ | Reference |
---|---|---|---|---|
DHEA | 1177 (breast cancer cells) 1259 (prostate cancer cells) | 1053 | 514 | [16] |
DHEA | - | 245 | 163 | [47] |
5-AED | 210 | 49 | 10 | [48] |
5-AED | - | 3.6 | 0.9 | [47] |
5-AED | - | 100 | 5 | [49] |
DHT | 0.5 (breast cancer cells) 0.52 (prostate cancer cells) | >5000 | 1687 | [16] |
DHT | - | 221 | 73 | [47] |
DHT | 15 | - | - | [48] |
Testosterone | 0.5 (breast cancer cells) 0.52 (prostate cancer cells) | >5000 | >500 | [16] |
E2 | 3.64 | 0.04 | 0.1 | [16] |
E2 | - | 8 | 7 | [48] |
E2 | - | 0.12 | 0.13 | [47] |
Clinical Parameter (Endpoint) | Trial 1: Intrarosa N = 81, Placebo N = 77 | Trial 2: Intrarosa N = 157, Placebo N = 325 |
---|---|---|
Dyspareunia Week 12 Mean Severity | −0.40 | −0.35 |
% Superficial Cells Week 12 Mean | 4.71 | 8.46 |
% Parabasal Cells Week 12 Mean | −45.77 | −29.53 |
Vaginal pH Week 12 Mean | −0.83 | −0.67 |
Androstene Chemical Name | Androstene Trade Name | Pharmacological Indication | Status | Reference or Link | |
---|---|---|---|---|---|
1 | 5-androstenediol | Tetragold, Neumune | Radioprotective agent | Investigational | [73,74,75] |
2 | DHEA | Prasterone | The treatment of dyspareunia associated with menopausal vulvar and vaginal atrophy | FDA approved | [59,60,61,62,63,64,65] |
3 | 3α-ethynyl-androst-5-ene-3β,7β,17β-triol | Triplex (ne3107) | Anti-inflammatory action: collagen-induced arthritis, Alzheimer’s disease, and Parkinson’s disease | Investigational | [76,77] |
4 | 17α,20R-epoxypregn-5-ene-3β,21-diol | BNN27 | Neuroprotector | Investigational | [78,79,80] |
5 | 3β-dehydroxy-16α-fluoro-DHEA | Fluasterone | Anti-inflammatory effects in preclinical models of chronic autoimmune diseases (psoriasis, asthma, rheumatoid arthritis, multiple sclerosis, and lupus erythematosus) and lastly for the control of hyperglycemia in adults with Cushing syndrome | Investigational | [81,82,83,84,85] |
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Fedotcheva, T.A.; Uspenskaya, M.E.; Ulchenko, D.N.; Shimanovsky, N.L. Dehydroepiandrosterone and Its Metabolite 5-Androstenediol: New Therapeutic Targets and Possibilities for Clinical Application. Pharmaceuticals 2024, 17, 1186. https://doi.org/10.3390/ph17091186
Fedotcheva TA, Uspenskaya ME, Ulchenko DN, Shimanovsky NL. Dehydroepiandrosterone and Its Metabolite 5-Androstenediol: New Therapeutic Targets and Possibilities for Clinical Application. Pharmaceuticals. 2024; 17(9):1186. https://doi.org/10.3390/ph17091186
Chicago/Turabian StyleFedotcheva, Tatiana A., Maria E. Uspenskaya, Darya N. Ulchenko, and Nikolay L. Shimanovsky. 2024. "Dehydroepiandrosterone and Its Metabolite 5-Androstenediol: New Therapeutic Targets and Possibilities for Clinical Application" Pharmaceuticals 17, no. 9: 1186. https://doi.org/10.3390/ph17091186