1.
Sources and Composition
1.1
Sources
Pygeum is a term used to refer to the bark of Prunus africanum (sometimes referred to as Pygeum africanum) that is used for medicinal purposes, usually from traditional african medicine for the purpose of benign prostatic hyperplasmia, particularly in Europe.[1][2] The tree itself is known as the African cherry tree and the fruits it bears are accordingly known as african cherries[3] or african plums.[4]
It is marketed in Italy (Pigenil) and France (Tadenan), with the latter being a combination product with Saw Palmetto in a 4:1 ratio to Pygeum bark. Pygeum appears to have a history of usage as Tadenan against Benign prostatic hyperplasia.[5]
Pygeum is derived from the tree bark of the african cherry tree, and has relatively recent usage against benign prostatic hyperplasia but originates from traditional african medicine
1.2
Composition
The bark of Pygeum tends to contain
- N-butylbenzenesulfonamide[6]
- Atraric acid[7]
- β-sitosterol (349-583mg/kg)[6][8] as well as β-sitostenone at 116–260 mg/kg[8]
- Fatty acids of mostly linoleic acid (30.6%), palmitic (28.3%), oleic (24.90%), and stearic (10.58%) with trace linolenic, lauric, and myristic acids[9]
- Docosanol[10] at 10-28mg/kg dry weight[8]
- Behenic acid, ursolic acid (highly variable at 317-2000mg/kg),[8] and lignoceric acid[10]
- Ferulic acid[11] at 30-90mg/kg[8]
- Friedelin may[12] or may not[8] be detectable above 7mg/kg
The bioactives are mostly thought to be fatty acids, and although the main bioactives are not currently known they are suspected to be the antiandrogenic N-butylbenzenesulfonamide and Atraric acid
2.
Pharmacology
2.1
Excretion
One study assessing the urine of men following consumption of Pygeum has found 4 compounds that were significantly altered. These compounds were unable to be named, although molecular weights or formula was recorded.[13]
2.2
Enzymatic Interactions
Pygeum extract has been found to inhibit the aromatase enzyme in vitro with an IC50 value of 780mcg/mL with some efficacy at 100mcg/mL, and a mixture of Pygeum and Stinging nettle failed to significant increase the potency of the IC50 value.[14]
5α-reductase has been found to be inhibited by Pygeum extract with an IC50 of 980mcg/mL, and was synergistic with Stinging Nettle (which inherently was weak in 5α-reductase inhibition, with the combination resulting in an IC50 of 240mcg/mL).[14]
3.
Interactions with Hormones
3.1
Androgens
In a competitive ligand binding assay, Pygeum has been found to displace approximately 60% of DHT from the androgen receptor at a concentration of 5uL/mL, with the beta-sitosterol molecule being inactive.[15] The active molecule may be N-butylbenzenesulfonamide, which has been noted elsewhere to be a component of Pygeum[6] and an androgen receptor antagonist[16] although atraric acid is also suspected.[7]
Atraric acid has an IC50 value around 3μM while it exerts no significant inhibitory effect at 0.1μM and at 10μM exerts about 90% inhibition of signalling.[7] N-butylbenzenesulfonamide requires 100μM to exert 90% inhibition and has an IC50 value of approximately 10μM.[17] These potencies are less than the reference drug casodex (IC50 of 1uM[18]) but greater than that of the reference drug flutamide (116uM).[18][16]
Testosterone binding was not tested,[15] although androgen receptor blockers should also hinder the signalling of testosterone.
Compounds in Pygeum appear to be androgen receptor _antagonist_s, which reduce signalling via the androgen receptor, and appears to be seemingly potent at this in vitro
3.2
Estrogen
In a mouse uterine cytosol (competitive ligand binding assay), Pygeum extract has been noted to displace 70% of estradiol from its receptor when Pygeum is at 5uL/mL concentration; this was not due to the beta-sitosterol content (which was inactive).[15] In PC-3 cells (prostatic cancer cells), a dose-dependent inhibition of signalling via the estrogen receptor (ERα) has been noted with Pygeum in the presence of estradiol[15] although it may activate signalling of the receptor when incubated in isolation.[19]
When investigating the two molecules known to have anti-androgenic effects, N-butylbenzenesulfonamide failed to activate the estogen receptor at the concentrations required to inhibit 90% of androgen receptor activity; at 10-fold higher concentrations, atraric acid had slight estrogenic effects.[17][20][16]
It is possible that Pygeum has a phytoestrogenic potential that interferes with estrogen signalling (which would establish it as a selective estrogen receptor modulator or SERM) but this is not fully elucidated or established in a living model
4.
Inflammation and Immunology
4.1
Mechanisms
In LPS-activated macrophages, the secretion of IL-6 has been noted to be abolished with Pygeum extract at the concentration of 100mcg/well, which was not significantly different than dexamethasone as active control; this study was confounded as the Pygeum product was a 4:1 ratio of Saw Palmetto and Pygeum.[21]
5.
Interactions with Organ Systems
5.1
Prostate
Pygeum extract has been noted to reduce the proliferation of prostatic fibroblasts and myofibroblasts in vitro (surgically obtained) with an ethanolic extract at 25mcg/mL, with near absolute inhibition of basal and both EGF/VEGF induced proliferation at 100mcg/mL, although this dose was minorly cytotoxic (highest effective concentration without cytotoxicity being established at 25-50mcg/mL).[22] This was then replicated with MDCK cells with dose-dependence also established with significance above 25mcg/mL,[22] and hindering the effects of these two growth factors on prostatic cells has been noted elsewhere[23] as well as hindering the growth promoting effects of IGF-1.[24]
One study comparing the efficacy of Pygeum extract on prostatic tissue (obtained surgically) in those with benign prostatic hyperplasia versus normal controls found that the extract, in vitro, was more effective in inhibiting the proliferation of hyperplasic cells (EC50 7.35µg/mL) relative to normal cells (EC50 18.68µg/mL) associated with a 7-fold reduction of TGFB1 mRNA in hyperplasic cells and [25]
These anti-proliferative effects have been confirmed in a human (n=1) during a preliminary assessment, where myofibroblast proliferation was reduced although there was no apparent effect on the prostatic epithelial cell line PNT2.[26]
Mechanistically, Pygeum may reduce prostatic cell proliferation and appears to be slightly more effective in cells undergoing benigin hyperplasia. Pygeum has been noted to interfere with prostatic growth factors
In regards to prostatic hyperplasia, a 2002 Cochrane meta-analysis[27] was able to note 18 trials comparing Pygeum (17 of which to placebo control) with no comparison against reference drugs; overall, the analysis of studies meeting inclusion criteria (minimal due to lack of extractable data, reducing the total sample of 1562 down to 430) noted that Pygeum was associated with a 19% reduction in nocturia that was not statistically significant (3 trials assessed with an effect size of -0.9 and 95% CI of -2.0 to 0.1), 24% improvement in residual urine volume (2 trials; effect size of 2.5 with a 95% CI of 0.3-5.0), and 23% increase in peak urine flow (4 trials; effect size of -13 with a 95% CI of -23 to -3).[27] Symptoms of benign prostatic hyperplasia, as assessed by physician, were reduced in the Pygeum group relative to placebo (5 trials assessed, 64% of patients reporting an improvement in symptoms in Pygeum relative to 30% in placebo);[27][28] this meta-analysis is duplicated in Medline.[29]
Beyond the meta-analysis, a trial using 25mg Pygeum (confounded with the inclusion of 300mg Stinging Nettle) has failed to benefit symptoms of prostatic hyperplasia to a larger degree than placebo treatment.[30] Another trial using this combination therapy has noted benefit, but measured the observed benefits relative to baseline rather than a placebo control.[31]
One trial using 50mg of Pygeum extract twice daily for 2 months in an open-label trial has noted that treatment with Pygeum is associated with reduced symptoms of Benign prostatic hyperplasia (40% reduction) and concomitant improvements in self-reported quality of life (32% improvement, although more variable) and reduction in nocturia (32%);[32] This trial did not have a placebo control,[32] and a subsequent study that was blinded but comparing 50mg twice daily against 100mg Pygeum daily for 2 months found that both were effective to similar degrees in reducing symptoms of benign prostatic hyperplasia and appeared to retain efficacy when held at the same dose over 10 months of an open-label follow-up period.[33]
There 'appears' to be a great deal of evidence as assessed by the meta-analysis mentioned previously, but a good deal of this evidence is not located online and appears to be intertwined with European usage of Pygeum as a phytopharmaceutical against Benign prostatic hyperplasia
When looking at the evidence in Pubmed, 50-100mg Pygeum supplementation daily is not clearly associated with beneficial effects on symptoms associated with benign prostatic hyperplasia
5.2
Bladder
Diabetic cystopathy is a condition affecting the bladders of diabetic persons which is characterized by abnormal functioning (decreased bladder sensation, poor contractility and increased post-void residual urine diagnosed with urodynamics, uroflow and measurement of post-void residual urine) although it appears to lack a precise definition and pathological understanding.[34][35][36] In general, it is bladder dysfunction associated with high blood sugar and/or insulin.
In diabetic rats fed 100mg/kg Pygeum extract for 4 weeks, Pygeum was associated with attentuating the changes observed in the bladder tissue of diabetic rats relative to control by approximately 50% (in reference to Maximal bladder volume and bladder pressure) which correlated with improvements in antioxidant enzyme concentrations and a reduction in iNOS expression in the urogenital region; there was no influence of Pygeum on serum glucose.[37]
6.
Interactions with Cancer Metabolism
6.1
Prostate
In vitro with PC-3 and LNCaP prostate cancer cells, the IC50 of Pygeum extract appears to be approximately 2.5mcg/mL and isolated beta-sitosterol was noted to inhibit LNCaP but not PC-3. These changes were associated with cell accumulation in S phase and increased apoptosis.[15]
A subsequent in vivo test using TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate[38]) mice designed to develop prostate cancer noted that the 62.5% occurrence of prostate cancer in control mice over 5 months was reduced to 35% in mice fed Pygeum (0.128g/kg).[15]
References
- ^Hutchison A, Farmer R, Verhamme K, Berges R, Navarrete RVThe efficacy of drugs for the treatment of LUTS/BPH, a study in 6 European countriesEur Urol.(2007 Jan)
- ^Edgar AD, Levin R, Constantinou CE, Denis LA critical review of the pharmacology of the plant extract of Pygeum africanum in the treatment of LUTSNeurourol Urodyn.(2007)
- ^Stewart KMThe African cherry (Prunus africana): can lessons be learned from an over-exploited medicinal treeJ Ethnopharmacol.(2003 Nov)
- ^Strong KMAfrican plum and benign prostatic hypertrophyJ Herb Pharmacother.(2004)
- ^Paubert-Braquet M, Cave A, Hocquemiller R, Delacroix D, Dupont C, Hedef N, Borgeat PEffect of Pygeum africanum extract on A23187-stimulated production of lipoxygenase metabolites from human polymorphonuclear cellsJ Lipid Mediat Cell Signal.(1994 May)
- ^Schleich S, Papaioannou M, Baniahmad A, Matusch RExtracts from Pygeum africanum and other ethnobotanical species with antiandrogenic activityPlanta Med.(2006 Jul)
- ^Schleich S, Papaioannou M, Baniahmad A, Matusch RActivity-guided isolation of an antiandrogenic compound of Pygeum africanumPlanta Med.(2006 May)
- ^Kadu CA, Parich A, Schueler S, Konrad H, Muluvi GM, Eyog-Matig O, Muchugi A, Williams VL, Ramamonjisoa L, Kapinga C, Foahom B, Katsvanga C, Hafashimana D, Obama C, Vinceti B, Schumacher R, Geburek TBioactive constituents in Prunus africana: geographical variation throughout Africa and associations with environmental and genetic parametersPhytochemistry.(2012 Nov)
- ^Ganzera M, Croom EM, Khan IADetermination of the Fatty Acid content of pumpkin seed, pygeum, and saw palmettoJ Med Food.(1999)
- ^Hass MA, Nowak DM, Leonova E, Levin RM, Longhurst PAIdentification of components of Prunus africana extract that inhibit lipid peroxidationPhytomedicine.(1999 Nov)
- ^Triterpenes from Prunus africana bark
- ^Catalano S, Ferretti M, Marsili A, Morelli INew constituents of Prunus africana bark extractJ Nat Prod.(1984 Sep-Oct)
- ^10 Metabolomics profiles of prostatic secretions from patients treated by Pygeum Africanum for low urinary tract symptoms related to benign prostatic hyperplasia
- ^Hartmann RW, Mark M, Soldati FInhibition of 5 α-reductase and aromatase by PHL-00801 (Prostatonin®), a combination of PY102 (Pygeum africanum) and UR102 (Urtica dioica) extractsPhytomedicine.(1996 Sep)
- ^Shenouda NS, Sakla MS, Newton LG, Besch-Williford C, Greenberg NM, MacDonald RS, Lubahn DBPhytosterol Pygeum africanum regulates prostate cancer in vitro and in vivoEndocrine.(2007 Feb)
- ^Roell D, Baniahmad AThe natural compounds atraric acid and N-butylbenzene-sulfonamide as antagonists of the human androgen receptor and inhibitors of prostate cancer cell growthMol Cell Endocrinol.(2011 Jan 30)
- ^Papaioannou M, Schleich S, Roell D, Schubert U, Tanner T, Claessens F, Matusch R, Baniahmad ANBBS isolated from Pygeum africanum bark exhibits androgen antagonistic activity, inhibits AR nuclear translocation and prostate cancer cell growthInvest New Drugs.(2010 Dec)
- ^Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D Jr, Farquhar R, Guo Z, Qiu Y, Brodie AMNovel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft modelJ Med Chem.(2005 Apr 21)
- ^Mathé G, Orbach-Arbouys S, Bizi E, Court BThe so-called phyto-estrogenic action of Pygeum africanum extractBiomed Pharmacother.(1995)
- ^Papaioannou M, Schleich S, Prade I, Degen S, Roell D, Schubert U, Tanner T, Claessens F, Matusch R, Baniahmad AThe natural compound atraric acid is an antagonist of the human androgen receptor inhibiting cellular invasiveness and prostate cancer cell growthJ Cell Mol Med.(2009 Aug)
- ^Bach SM, Perotti ME, Merep AP, Marcial GE, Grau A, Attarian R, Av-Gay Y, Bach H, Catalán CAChemical constituents, anti-inflammatory and antioxidant activities of bark extracts from Prunus tucumanensis LilloNat Prod Res.(2012 Mar 9)
- ^Boulbès D, Soustelle L, Costa P, Haddoum M, Bali JP, Hollande F, Magous RPygeum africanum extract inhibits proliferation of human cultured prostatic fibroblasts and myofibroblastsBJU Int.(2006 Nov)
- ^Inhibition of bFGF and EGF-induced proliferation of 3T3 fibroblasts by extract of Pygeum africanum (Tadenan®)
- ^Yablonsky F, Nicolas V, Riffaud JP, Bellamy FAntiproliferative effect of Pygeum africanum extract on rat prostatic fibroblastsJ Urol.(1997 Jun)
- ^Quiles MT, Arbós MA, Fraga A, de Torres IM, Reventós J, Morote JAntiproliferative and apoptotic effects of the herbal agent Pygeum africanum on cultured prostate stromal cells from patients with benign prostatic hyperplasia (BPH)Prostate.(2010 Jul 1)
- ^Larré S, Camparo P, Comperat E, Boulbés D, Haddoum M, Baulande S, Soularue P, Costa P, Cussenot OBiological effect of human serum collected before and after oral intake of Pygeum africanum on various benign prostate cell culturesAsian J Androl.(2012 May)
- ^Wilt T, Ishani A, Mac Donald R, Rutks I, Stark GPygeum africanum for benign prostatic hyperplasiaCochrane Database Syst Rev.(2002)
- ^Barry MReview: Pygeum africanum extracts improve symptoms and urodynamics in symptomatic benign prostatic hyperplasiaACP J Club.(2002 Sep-Oct)
- ^Ishani A, MacDonald R, Nelson D, Rutks I, Wilt TJPygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysisAm J Med.(2000 Dec 1)
- ^Melo EA, Bertero EB, Rios LA, Mattos D JrEvaluating the efficiency of a combination of Pygeum africanum and stinging nettle (Urtica dioica) extracts in treating benign prostatic hyperplasia (BPH): double-blind, randomized, placebo controlled trialInt Braz J Urol.(2002 Sep-Oct)
- ^Krzeski T, Kazón M, Borkowski A, Witeska A, Kuczera JCombined extracts of Urtica dioica and Pygeum africanum in the treatment of benign prostatic hyperplasia: double-blind comparison of two dosesClin Ther.(1993 Nov-Dec)
- ^Breza J, Dzurny O, Borowka A, Hanus T, Petrik R, Blane G, Chadha-Boreham HEfficacy and acceptability of tadenan (Pygeum africanum extract) in the treatment of benign prostatic hyperplasia (BPH): a multicentre trial in central EuropeCurr Med Res Opin.(1998)
- ^Chatelain C, Autet W, Brackman FComparison of once and twice daily dosage forms of Pygeum africanum extract in patients with benign prostatic hyperplasia: a randomized, double-blind study, with long-term open label extensionUrology.(1999 Sep)
- ^Kaplan SA, Blaivas JGDiabetic cystopathyJ Diabet Complications.(1988 Jul-Sep)
- ^Urologic Complications of Diabetes
- ^Diabetic Cystopathy—What Does it Mean?
- ^Wang D, Li Y, Hou G, Wang P, Zhang J, Laudon V, Shi BPygeum africanum: effect on oxidative stress in early diabetes-induced bladderInt Urol Nephrol.(2010 Jun)
- ^Foster BA, Gingrich JR, Kwon ED, Madias C, Greenberg NMCharacterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) modelCancer Res.(1997 Aug 15)