Androstenediol (original) (raw)

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Chemical compound

Androstenediol
Clinical data
Other names A5; Δ5-Diol; Androstenediol; Androst-5-ene-3β,17β-diol; Hermaphrodiol; HE2100
Routes of administration By mouth
Drug class Androgen; Anabolic steroid
Identifiers
IUPAC name (3_S_,8_R_,9_S_,10_R_,13_S_,14_S_,17_S_)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1_H_-cyclopenta[_a_]phenanthrene-3,17-diol
CAS Number 521-17-5 checkY
PubChem CID 10634
DrugBank DB01524 checkY
ChemSpider 10188 checkY
UNII 95PS51EMXY
KEGG C04295
ChEBI CHEBI:2710 checkY
ChEMBL ChEMBL440283 checkY
CompTox Dashboard (EPA) DTXSID9022609 Edit this at Wikidata
ECHA InfoCard 100.007.553 Edit this at Wikidata
Chemical and physical data
Formula C19H30O2
Molar mass 290.447 g·mol−1
3D model (JSmol) Interactive image
SMILES O[C@@H]4C/C3=C/C[C@@H]1[C@H](CC[C@@]2([C@@H](O)CC[C@@H]12)C)[C@@]3(C)CC4
InChI InChI=1S/C19H30O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h3,13-17,20-21H,4-11H2,1-2H3/t13-,14-,15-,16-,17-,18-,19-/m0/s1 checkYKey:QADHLRWLCPCEKT-LOVVWNRFSA-N checkY
(verify)

Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepiandrosterone (DHEA). It is closely related to androstenedione (androst-4-ene-3,17-dione).

Biological activity

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Androstenediol is a direct metabolite of the most abundant steroid produced by the human adrenal cortex, DHEA. It is less androgenic than the related compound, Δ4-androstenediol, and has been found to stimulate the immune system. When administered to rats, androstenediol, in vivo, has approximately 1.4% of the androgenicity of DHEA, 0.54% of the androgenicity of androstenedione, and 0.21% of the androgenicity of testosterone.[1]

Androstenediol possesses potent estrogenic activity, similarly to DHEA and 3β-androstanediol.[2] It has approximately 6% and 17% of the affinity of estradiol at the ERα and ERβ, respectively.[3] Although androstenediol has far lower affinity for the ERs compared to the major estrogen estradiol, it circulates at approximately 100-fold higher concentrations, and so is thought may play a significant role as an estrogen in the body.[4]

vte Affinities of estrogen receptor ligands for the ERα and ERβ

Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)a Action
ERα ERβ ERα ERβ
Estradiol E2; 17β-Estradiol 100 100 0.115 (0.04–0.24) 0.15 (0.10–2.08) Estrogen
Estrone E1; 17-Ketoestradiol 16.39 (0.7–60) 6.5 (1.36–52) 0.445 (0.3–1.01) 1.75 (0.35–9.24) Estrogen
Estriol E3; 16α-OH-17β-E2 12.65 (4.03–56) 26 (14.0–44.6) 0.45 (0.35–1.4) 0.7 (0.63–0.7) Estrogen
Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen
Alfatradiol 17α-Estradiol 20.5 (7–80.1) 8.195 (2–42) 0.2–0.52 0.43–1.2 Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol 7.795 (4.94–63) 50 ? ? Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol 55.45 (29–103) 79–80 ? ? Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite
2-Hydroxyestradiol 2-OH-E2 22 (7–81) 11–35 2.5 1.3 Metabolite
2-Methoxyestradiol 2-MeO-E2 0.0027–2.0 1.0 ? ? Metabolite
4-Hydroxyestradiol 4-OH-E2 13 (8–70) 7–56 1.0 1.9 Metabolite
4-Methoxyestradiol 4-MeO-E2 2.0 1.0 ? ? Metabolite
2-Hydroxyestrone 2-OH-E1 2.0–4.0 0.2–0.4 ? ? Metabolite
2-Methoxyestrone 2-MeO-E1 <0.001–<1 <1 ? ? Metabolite
4-Hydroxyestrone 4-OH-E1 1.0–2.0 1.0 ? ? Metabolite
4-Methoxyestrone 4-MeO-E1 <1 <1 ? ? Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol 2.0–6.5 35 ? ? Metabolite
2-Hydroxyestriol 2-OH-E3 2.0 1.0 ? ? Metabolite
4-Methoxyestriol 4-MeO-E3 1.0 1.0 ? ? Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate <1 <1 ? ? Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate 0.0004 ? ? ? Metabolite
Estradiol 3-glucuronide E2-3G 0.0079 ? ? ? Metabolite
Estradiol 17β-glucuronide E2-17G 0.0015 ? ? ? Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S 0.0001 ? ? ? Metabolite
Estrone sulfate E1S; Estrone 3-sulfate <1 <1 >10 >10 Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate 10 ? ? ? Estrogen
Estradiol 17β-benzoate E2-17B 11.3 32.6 ? ? Estrogen
Estrone methyl ether Estrone 3-methyl ether 0.145 ? ? ? Estrogen
_ent_-Estradiol 1-Estradiol 1.31–12.34 9.44–80.07 ? ? Estrogen
Equilin 7-Dehydroestrone 13 (4.0–28.9) 13.0–49 0.79 0.36 Estrogen
Equilenin 6,8-Didehydroestrone 2.0–15 7.0–20 0.64 0.62 Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol 7.9–113 7.9–108 0.09 0.17 Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol 18.6 (18–41) 14–32 0.24 0.57 Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol 35–68 90–100 0.15 0.20 Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol 20 49 0.50 0.37 Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol 68 72 0.15 0.25 Estrogen
Δ8-Estrone 8,9-Dehydroestrone 19 32 0.52 0.57 Estrogen
Ethinylestradiol EE; 17α-Ethynyl-17β-E2 120.9 (68.8–480) 44.4 (2.0–144) 0.02–0.05 0.29–0.81 Estrogen
Mestranol EE 3-methyl ether ? 2.5 ? ? Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE 35–43 5–20 0.5 2.6 Estrogen
Methylestradiol 17α-Methyl-17β-estradiol 70 44 ? ? Estrogen
Diethylstilbestrol DES; Stilbestrol 129.5 (89.1–468) 219.63 (61.2–295) 0.04 0.05 Estrogen
Hexestrol Dihydrodiethylstilbestrol 153.6 (31–302) 60–234 0.06 0.06 Estrogen
Dienestrol Dehydrostilbestrol 37 (20.4–223) 56–404 0.05 0.03 Estrogen
Benzestrol (B2) – 114 ? ? ? Estrogen
Chlorotrianisene TACE 1.74 ? 15.30 ? Estrogen
Triphenylethylene TPE 0.074 ? ? ? Estrogen
Triphenylbromoethylene TPBE 2.69 ? ? ? Estrogen
Tamoxifen ICI-46,474 3 (0.1–47) 3.33 (0.28–6) 3.4–9.69 2.5 SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT 100.1 (1.7–257) 10 (0.98–339) 2.3 (0.1–3.61) 0.04–4.8 SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ? 7.14–20.3 15.4 SERM
Clomifene MRL-41 25 (19.2–37.2) 12 0.9 1.2 SERM
Cyclofenil F-6066; Sexovid 151–152 243 ? ? SERM
Nafoxidine U-11,000A 30.9–44 16 0.3 0.8 SERM
Raloxifene – 41.2 (7.8–69) 5.34 (0.54–16) 0.188–0.52 20.2 SERM
Arzoxifene LY-353,381 ? ? 0.179 ? SERM
Lasofoxifene CP-336,156 10.2–166 19.0 0.229 ? SERM
Ormeloxifene Centchroman ? ? 0.313 ? SERM
Levormeloxifene 6720-CDRI; NNC-460,020 1.55 1.88 ? ? SERM
Ospemifene Deaminohydroxytoremifene 0.82–2.63 0.59–1.22 ? ? SERM
Bazedoxifene – ? ? 0.053 ? SERM
Etacstil GW-5638 4.30 11.5 ? ? SERM
ICI-164,384 – 63.5 (3.70–97.7) 166 0.2 0.08 Antiestrogen
Fulvestrant ICI-182,780 43.5 (9.4–325) 21.65 (2.05–40.5) 0.42 1.3 Antiestrogen
Propylpyrazoletriol PPT 49 (10.0–89.1) 0.12 0.40 92.8 ERα agonist
16α-LE2 16α-Lactone-17β-estradiol 14.6–57 0.089 0.27 131 ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol 30.2 2.30 ? ? ERα agonist
Methylpiperidinopyrazole MPP 11 0.05 ? ? ERα antagonist
Diarylpropionitrile DPN 0.12–0.25 6.6–18 32.4 1.7 ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol 0.35 22.0–83 12.9 0.50 ERβ agonist
Prinaberel ERB-041; WAY-202,041 0.27 67–72 ? ? ERβ agonist
ERB-196 WAY-202,196 ? 180 ? ? ERβ agonist
Erteberel SERBA-1; LY-500,307 ? ? 2.68 0.19 ERβ agonist
SERBA-2 – ? ? 14.5 1.54 ERβ agonist
Coumestrol – 9.225 (0.0117–94) 64.125 (0.41–185) 0.14–80.0 0.07–27.0 Xenoestrogen
Genistein – 0.445 (0.0012–16) 33.42 (0.86–87) 2.6–126 0.3–12.8 Xenoestrogen
Equol – 0.2–0.287 0.85 (0.10–2.85) ? ? Xenoestrogen
Daidzein – 0.07 (0.0018–9.3) 0.7865 (0.04–17.1) 2.0 85.3 Xenoestrogen
Biochanin A – 0.04 (0.022–0.15) 0.6225 (0.010–1.2) 174 8.9 Xenoestrogen
Kaempferol – 0.07 (0.029–0.10) 2.2 (0.002–3.00) ? ? Xenoestrogen
Naringenin – 0.0054 (<0.001–0.01) 0.15 (0.11–0.33) ? ? Xenoestrogen
8-Prenylnaringenin 8-PN 4.4 ? ? ? Xenoestrogen
Quercetin – <0.001–0.01 0.002–0.040 ? ? Xenoestrogen
Ipriflavone – <0.01 <0.01 ? ? Xenoestrogen
Miroestrol – 0.39 ? ? ? Xenoestrogen
Deoxymiroestrol – 2.0 ? ? ? Xenoestrogen
β-Sitosterol – <0.001–0.0875 <0.001–0.016 ? ? Xenoestrogen
Resveratrol – <0.001–0.0032 ? ? ? Xenoestrogen
α-Zearalenol – 48 (13–52.5) ? ? ? Xenoestrogen
β-Zearalenol – 0.6 (0.032–13) ? ? ? Xenoestrogen
Zeranol α-Zearalanol 48–111 ? ? ? Xenoestrogen
Taleranol β-Zearalanol 16 (13–17.8) 14 0.8 0.9 Xenoestrogen
Zearalenone ZEN 7.68 (2.04–28) 9.45 (2.43–31.5) ? ? Xenoestrogen
Zearalanone ZAN 0.51 ? ? ? Xenoestrogen
Bisphenol A BPA 0.0315 (0.008–1.0) 0.135 (0.002–4.23) 195 35 Xenoestrogen
Endosulfan EDS <0.001–<0.01 <0.01 ? ? Xenoestrogen
Kepone Chlordecone 0.0069–0.2 ? ? ? Xenoestrogen
_o,p'_-DDT – 0.0073–0.4 ? ? ? Xenoestrogen
_p,p'_-DDT – 0.03 ? ? ? Xenoestrogen
Methoxychlor _p,p'_-Dimethoxy-DDT 0.01 (<0.001–0.02) 0.01–0.13 ? ? Xenoestrogen
HPTE Hydroxychlor; _p,p'_-OH-DDT 1.2–1.7 ? ? ? Xenoestrogen
Testosterone T; 4-Androstenolone <0.0001–<0.01 <0.002–0.040 >5000 >5000 Androgen
Dihydrotestosterone DHT; 5α-Androstanolone 0.01 (<0.001–0.05) 0.0059–0.17 221–>5000 73–1688 Androgen
Nandrolone 19-Nortestosterone; 19-NT 0.01 0.23 765 53 Androgen
Dehydroepiandrosterone DHEA; Prasterone 0.038 (<0.001–0.04) 0.019–0.07 245–1053 163–515 Androgen
5-Androstenediol A5; Androstenediol 6 17 3.6 0.9 Androgen
4-Androstenediol – 0.5 0.6 23 19 Androgen
4-Androstenedione A4; Androstenedione <0.01 <0.01 >10000 >10000 Androgen
3α-Androstanediol 3α-Adiol 0.07 0.3 260 48 Androgen
3β-Androstanediol 3β-Adiol 3 7 6 2 Androgen
Androstanedione 5α-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Etiocholanedione 5β-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Methyltestosterone 17α-Methyltestosterone <0.0001 ? ? ? Androgen
Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol 4.0 <0.07 ? ? Estrogen
Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol 50 5.6 ? ? Estrogen
Progesterone P4; 4-Pregnenedione <0.001–0.6 <0.001–0.010 ? ? Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT 0.085 (0.0015–<0.1) 0.1 (0.01–0.3) 152 1084 Progestogen
Norethynodrel 5(10)-Norethisterone 0.5 (0.3–0.7) <0.1–0.22 14 53 Progestogen
Tibolone 7α-Methylnorethynodrel 0.5 (0.45–2.0) 0.2–0.076 ? ? Progestogen
Δ4-Tibolone 7α-Methylnorethisterone 0.069–<0.1 0.027–<0.1 ? ? Progestogen
3α-Hydroxytibolone – 2.5 (1.06–5.0) 0.6–0.8 ? ? Progestogen
3β-Hydroxytibolone – 1.6 (0.75–1.9) 0.070–0.1 ? ? Progestogen
Footnotes: a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Androstenediol, also known as androst-5-ene-3β,17β-diol, is a naturally occurring androstane steroid.[5] It is closely related structurally to androstenedione (A4; androst-4-ene-3,17-dione), dehydroepiandrosterone (DHEA; androst-5-en-3β-ol-17-one), and testosterone (androst-4-en-17β-ol-3-one), as well as to 3β-androstanediol (5α-androstane-3β,17β-diol).[5]

Derivatives and analogues of androstenediol, such as the 17α-substituted methandriol (17α-methylandrostenediol) and ethinylandrostenediol (17α-ethynylandrostenediol) as well as the naturally occurring 19-norandrostane derivative norandostenediol (19-nor-5-androstenediol), have been synthesized and studied. Methandriol and its esters are androgens and anabolic steroids while ethinylandrostenediol is an estrogen.

Radiation countermeasure

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Androstenediol has been investigated for use as a radiation countermeasure. Its value as a radiation countermeasure is based mainly on its stimulation of production of white blood cells and platelets.[6] Its potential use as a radiation countermeasure was developed by the Armed Forces Radiobiology Research Institute (AFRRI) and subsequently studied by AFRRI and Hollis-Eden Pharmaceuticals under the proposed brand name Neumune for the treatment of acute radiation syndrome.[6][7]

The clinical trials with rhesus monkeys were successful. According to the Hollis-Eden report, only 12.5% of the 40 Neumune-treated animals died versus 32.5% in the placebo group.[8]

Hollis-Eden had applied for a contract from the U.S. Government under the BioShield Request for Proposals (RFP) for radiation countermeasures. After being encouraged for 2.5 years that Neumune was in the competitive range, on March 9, 2007, the RFP was canceled by HHS. According to HHS, "the product was no longer in the competitive range".[9][10] No further explanation was given. As a result, Hollis-Eden has now withdrawn from the radiation countermeasure field.

Steroidogenesis, with androstenediol at bottom left.

  1. ^ Coffey DS (1988). "Androgen action and the sex accessory tissues". In Knobil E, Neill J (eds.). The Physiology of Reproduction. New York: Raven Press. pp. 1081–1119.
  2. ^ Hackenberg R, Turgetto I, Filmer A, Schulz KD (November 1993). "Estrogen and androgen receptor mediated stimulation and inhibition of proliferation by androst-5-ene-3 beta,17 beta-diol in human mammary cancer cells". The Journal of Steroid Biochemistry and Molecular Biology. 46 (5): 597–603. doi:10.1016/0960-0760(93)90187-2. PMID 8240982. S2CID 54256515.
  3. ^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (March 1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–870. doi:10.1210/endo.138.3.4979. PMID 9048584.
  4. ^ Bradbury R (30 January 2007). Cancer. Springer Science & Business Media. pp. 43–. ISBN 978-3-540-33120-9.
  5. ^ a b Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 86–. ISBN 978-1-4757-2085-3.
  6. ^ a b Whitnall MH, Elliott TB, Harding RA, Inal CE, Landauer MR, Wilhelmsen CL, McKinney L, Miner VL, Jackson WE 3rd, Loria RM, Ledney GD, Seed TM (2000). "Androstenediol stimulates myelopoiesis and enhances resistance to infection in gamma-irradiated mice". Int. J. Immunopharmacol. 22 (1): 1–14. doi:10.1016/s0192-0561(99)00059-4. PMID 10684984.
  7. ^ Grace MB, Singh VK, Rhee JG, Jackson WE 3rd, Kao TC, Whitnall MH (2012). "5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis". J. Radiat. Res. 53 (6): 840–853. doi:10.1093/jrr/rrs060. PMC 3483857. PMID 22843381.
  8. ^ Hollis-Eden Pharmaceuticals Reports Publication of Results Demonstrating the Ability of NEUMUNE(R) to Increase Survival in a Primate Model of Lethal Radiation Injury, February 26, 2007.
  9. ^ Government Nukes Hollis-Eden's Radiation Drug, by Val Brickates Kennedy and Angela Moore, March 8, 2007
  10. ^ US cancels radiation contract with Hollis-Eden Archived 2007-09-12 at archive.today, March 9, 2007