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Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: A randomized, placebo-controlled, double-blind, crossover study


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This randomized-controlled trial examined the efficacy of wonderful variety pomegranate juice versus placebo in improving erections in 53 completed subjects with mild to moderate erectile dysfunction. The crossover design consisted of two 4-week treatment periods separated by a 2-week washout. Efficacy was assessed using International Index of Erectile Function (IIEF) and Global Assessment Questionnaires (GAQ). Of the 42 subjects who demonstrated improvement in GAQ scores after beverage consumption, 25 reported improvement after drinking pomegranate juice. Further, 17 subjects showed preference of one beverage to the other. Subjects were more likely to have improved scores when pomegranate juice was consumed (P=0.058). Although overall statistical significance was not achieved, this pilot study suggests the possibility that larger cohorts and longer treatment periods may achieve statistical significance.
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Efficacy and safety of pomegranate juice on improvement
of erectile dysfunction in male patients with mild to moderate
erectile dysfunction: a randomized, placebo-controlled,
double-blind, crossover study
CP Forest
, H Padma-Nathan
and HR Liker
The Male Clinic, Beverly Hills, CA, USA and
David Geffen School of Medicine at University of California, Los Angeles,
This randomized-controlled trial examined the efficacy of wonderful variety pomegranate juice
versus placebo in improving erections in 53 completed subjects with mild to moderate erectile
dysfunction. The crossover design consisted of two 4-week treatment periods separated by a 2-week
washout. Efficacy was assessed using International Index of Erectile Function (IIEF) and Global
Assessment Questionnaires (GAQ). Of the 42 subjects who demonstrated improvement in GAQ
scores after beverage consumption, 25 reported improvement after drinking pomegranate juice.
Further, 17 subjects showed preference of one beverage to the other. Subjects were more likely to
have improved scores when pomegranate juice was consumed (P ¼ 0.058). Although overall
statistical significance was not achieved, this pilot study suggests the possibility that larger cohorts
and longer treatment periods may achieve statistical significance.
International Journal of Impotence Research (2007) 19, 564–567; doi:10.1038/sj.ijir.3901570;
published online 14 June 2007
Keywords: erectile dysfunction; pomegranate juice; antioxidants; endothelial function; nitric oxide
Pomegranate juice (POM) a potent antioxidant,
enhances endothelial nitric oxide (NO) levels and
directly impacts atherosclerotic changes associated
with erectile dysfunction (ED). The juice from
pomegranates contains potent polyphenolic flavo-
noid antioxidants known as anthocyanins. Studies
demonstrate that POM has more polyphenol antiox-
idants than any other fruit juice tested for antioxidant
activity. It has also been demonstrated to have greater
antioxidant activity than green tea or wine. POM
contains approximately 1.5% flavonoids, polyphe-
nols, pectin and ascorbic acid by weight.
Antioxidants, such as those in POM, enhance the
bioavailability of NO and offer protection against
Recent laboratory tests revealed
that POM consumption in atherosclerotic apolipo-
protein E-deficient mice reduced the size of athero-
sclerotic lesions by 44% and decreased low-density
lipoprotein (LDL) susceptibility to aggregation and
retention in humans.
The protective effects of NO
on atherosclerosis and oxidative destruction are
attributed to its ability to prevent adhesion and
aggregation of blood cells and platelets, inhibit
vascular smooth muscle cell proliferation, and
prevent oxidation of LDL cholesterol.
LDL choles-
terol that has been oxidized is much more likely to
become arterial plaque, therefore, by reducing LDL
oxidation in mice, POM reduces arterial plaque. One
study in humans demonstrated that POM consump-
tion significantly reduced common carotid intima-
media thickness associated with carotid artery
stenosis, along with concomitant lowering of blood
pressure and inhibition of lipid peroxidation in
serum and in LDL.
Because erectile tumescence and rigidity require
significant dilatation of the penile arteries, NO
deficiency may manifest itself as ED, the first
clinical manifestation of atherosclerotic disease.
Received 15 November 2006; revised 25 April 2007;
accepted 26 April 2007; published online 14 June 2007
Correspondence: Dr CP Forest, The Male Clinic, 9100
Wilshire Blvd., Suit 350, East Tower, Beverly Hills,
CA 90212,USA.
International Journal of Impotence Research (2007) 19, 564567
2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00
Owing to its effect on NO, antioxidants may play a
role in smooth muscle relaxation as well. Studies
demonstrate that POM, improves erectile function
and decreases fibrosis in animal models.
with its inherent antioxidant properties, has poten-
tial benefit for ED due to its ability to decrease
fibrosis, increase NO bioavailability and reduce
atherosclerotic plaque.
This randomized-controlled trial explores the
clinical efficacy of POM for the management of ED.
The primary hypothesis is that treatment of ED
patients with POM Wonderful POM would produce
statistically significant positive Global Assessment
Questionnaire (GAQ) scores when compared to
placebo-controlled patients. The GAQ elicits the
patient’s self-evaluation of study beverage effect on
erectile activity during that period. The secondary
hypothesis is that treatment of ED patients with
POM Wonderful POM would produce changes in
the erectile function domain of the International
Index of Erectile Function (IIEF) as well as the
remaining IIEF domains (intercourse satisfaction,
overall satisfaction, orgasm and desire domains)
when these values are compared with baseline and
between the two treatment groups. The IIEF is a
validated questionnaire whose erectile function
domain score has been demonstrated to correlate
with ED intensity.
Other domains of the IIEF were
evaluated as secondary end points.
Materials and methods
Study design and entrance criteria
This randomized, double-blind, placebo-controlled
clinical trial utilized a crossover design to compare
the efficacy of POM to placebo. Sixty sexually
active, healthy males aged 21–70 years with a
history of ED for at least 3 months duration were
recruited at a single site. To qualify, subjects were
required to have mild to moderate ED as indicated
by an erectile function domain score of 17–25 on the
IIEF Questionnaire.
Inclusion criteria included
being in a stable, monogamous relationship with a
consenting female partner and being willing to
attempt sexual intercourse on at least one occasion
per week during each study period. Subjects
were excluded from entrance into the study for
the following reasons: ED caused by untreated
endocrine disease, significant penile pathology,
clinically significant hepatic, renal or neurological
disease, a recent history of myocardial infarction,
diabetes mellitus or an HbA1cX7.0, history
of prostate cancer or prostate surgery other than a
transurethral resection of the prostate, a history of
alcoholism within the previous 2 years, or the
current consumption of three or more alcoholic
drinks per day. Any subject currently on ED
therapy (prescription medications, over-the-counter
medications, herbal preparations or medical
devices) was required to discontinue therapy during
the screening period and for the duration of the
Study event timeline
The study was designed to incorporate a screening
period for verification of eligibility followed by two
28-day treatment periods and a 14-day washout after
period 1. At visit 1, before all screening procedures,
the subject completed the IRB approved informed
consent process. A general medical and ED history
was obtained, a physical exam and laboratory
evaluations were performed, and the IIEF question-
naire was administered. Once it was determined
that a subject met inclusion criteria for entrance
into the study, he was scheduled to return for
At visit 2, immediately before randomization, the
subject was dosed with a sample containing 4
ounces of each beverage to verify tolerance. The
subject was subsequently randomized to either
placebo juice or POM for period 1. Subjects were
instructed to consume the entire 8 ounces of
beverage on a daily basis with their evening meal
or shortly after. The quantity of beverage required
was based upon human research, which indicated
that 1.5 mmol of total polyphenols is the optimal
dose per day.
At the end of 28 days of daily
consumption the subject returned for visit 3, where
the GAQ and IIEF were administered to assess the
effect of the period 1 study beverage on the subject’s
erectile function. A 2-week washout period ensued
during which time the subject did not consume any
study beverage nor utilize any treatment for ED. The
subject was provided with the opposite study
beverage during study period 2 as per the crossover
design of the study. Upon completion of 28 days of
consumption of the study beverage, the subject
returned for his final visit, where GAQ and IIEF
questionnaires were administered again to assess
the study beverage effect during the second study
Of the 74 subjects who entered the screening
process, 61 were enrolled and 53 completed the
study. Subjects with mild to moderate ED were
randomized into two cohorts, 31 subjects in cohort 1
and 30 in cohort 2. During period 1, subjects in
cohort 1 received the study beverage while those in
cohort 2 received placebo. Beverage assignments
were reversed during period 2 per crossover design.
At least 87% of subjects in each cohort consumed
the study beverage a minimum of 21 days during
each 28-day study period. Four subjects in cohort 1
Efficacy and safety of pomegranate juice
CP Forest et al
International Journal of Impotence Research
and three subjects in cohort 2 were lost to follow-up;
one subject discontinued for reasons not related to
the study. The mean age for each cohort was 46 years
old (46.39 in cohort 1; 45.97 in cohort 2) and the
mean IIEF score was 21 (20.84 in cohort 1; 20.73 in
cohort 2). No serious adverse events occurred during
the study and no subjects discontinued due to
adverse events. The most commonly reported
adverse events were upper respiratory infections
and pharyngitis (8% for POM; 4% for placebo). The
following adverse events were reported while on
POM: diarrhea (2%), flatulence (2%), hyperlipidemia
(2%), nasal congestion (2%) and hypertension
(2%). One patient (2%) reported anxiety while on
Of the 55 subjects who drank the placebo
beverage, 53 also drank POM. A total of 42 subjects
demonstrated improvement in GAQ score after
beverage consumption, 25 after drinking POM. In
total, 17 subjects showed preference of one beverage
to the other in GAQ scores. Of the 17 subjects, 8
from cohort 1 and 5 from cohort 2 preferred POM to
placebo while 2 subjects from each cohort preferred
placebo to POM. It was observed that subjects were
more likely to have improved scores if they drank
POM (P ¼ 0.058). It was noted that a higher propor-
tion of subjects showed improved GAQ scores in
cohort 1 (56 and 33%) than in cohort 2 (38 and
29%). Beverage preferred statistical analyses were
performed for the overall beverage comparisons
without controlling for age group. They utilized
the Mainland-Gart test for phase or beverage
preference, considering both cohort and period.
Beverage preferred is defined as POM when the
GAQ response was improved following the POM
beverage phase, but not after placebo beverage phase
and similarly for placebo (Table 1). Subjects with
missing or the same response for both phases were
not considered to have a preference (Table 2).
Secondary efficacy end points did not reach
clinical significance. The mean7s.d. of change from
baseline in IIEF erectile function domain score was
0.1376.08 for POM and 0.0275.04 for placebo
(P ¼ 0.72). The mean7s.d. of change from baseline
in IIEF of other domains was 1.4077.88 for POM
and 1.6476.88 for placebo.
Endothelial dysfunction has been closely associated
with atherosclerotic disease and compromises the
availability of NO in the penile tissues necessary to
cause smooth muscle relaxation and the resultant
tumescence and rigidity. Increasing the availability
of endothelium-derived NO is believed to increase
ultimately erectile response. PDE5 inhibitors, first-
line therapy for ED, prevent the breakdown of cyclic
GMP (cGMP) while appearing to facilitate local
NO release in the tissues with resultant erectile
response. POM has been demonstrated to contain
the highest potency of antioxidants when compared
to other beverages, enhancing the action of NO by
vascular endothelial cells. This study explored
whether the known antioxidant activity of POM
translates into clinical efficacy in healthy male
subjects with mild or mild-to-moderate ED.
This study observed trends toward increased
erectile function based on self-administered ques-
tionnaires, although overall statistical significance
was not achieved (P ¼ 0.058). Cohort 1 subjects
performed differently from cohort 2 even though
they shared similar demographic and baseline
characteristics (except remaining IIEF domain
score). Why subjects from cohort 1 were more likely
to have improved GAQ scores is unclear.
While improved scores on GAQ approached
statistical significance, the scores on the IIEF
questionnaire did not. It is important to note that
the GAQ is an assessment of the final result of 4
weeks of beverage consumption, while the IIEF
Table 1 Subjects demonstrating improvement in GAQ scores
Cohort (sequence) POM Placebo
1. (POM-Placebo) 15 (56%) 9 (33%)
2. (Placebo-POM) 10 (38%) 8 (29%)
Total 25 (47%) 17 (31%)
Abbreviations: GAQ, Global Assessment Questionnaire; POM,
pomegranate juice.
A total of 55 subjects drank Placebo; 53 of them drank POM.
Table 2 Compliance data for consumption of study beverage
Cohort 1 (n ¼ 31) Cohort 2 (n ¼ 30)
Period 1 Period 2 Period 1 Period 2
Number of study beverages consumed Mean7s.d. 32.373.8 34.578.5 32.472.9 32.573.5
Number of subjects consuming at least 21 bottles of study beverage n (%) 27 (87%) 27 (87%) 28 (93%) 26 (87%)
Number of subjects consuming 8–20 bottles of study beverage n (%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Number of subjects consuming o8 bottles of study beverage n (%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Number of subjects with missing beverage consumption data n (%) 4 (13%) 4 (13%) 2 (7%) 4 (13%)
Efficacy and safety of pomegranate juice
CP Forest et al
International Journal of Impotence Research
takes into consideration all sexual activity during
the previous 4 weeks. If the POM required as much
as 2 weeks of consumption before demonstrating a
response based upon recent studies,
then the IIEF
would not be as sensitive to recognizing an
improvement in erectile function as the GAQ. The
use of a subject sexual encounter diary would have
been useful in this situation to demonstrate if there
was progressive improvement in erectile function
during each treatment period.
The limitations of this pilot study include cohort
size, treatment period duration, and compliance
issues. Considering that the P-value nearly achieved
statistical significance (0.058) for those who pre-
ferred POM, it is possible that statistical significance
could have been achieved with either larger cohorts
of subjects or extended treatment periods. It was
proposed at the onset of the study that the clinical
effect of POM on ED could be observed as quickly as
within a week, yet this may not have been long
enough time to allow for a clinical response.
Extended treatment periods could provide the time
necessary to observe improved clinical response and
thus improved GAQ and IIEF scores. Study visit
compliance among many subjects was difficult and
required multiple telephone contacts to insure
maintenance of visits within windows. This was
anticipated since compliance issues are common in
clinical trials involving young healthy men (study
mean age of 46). This is largely related to the
commitment and activity levels in this age group. A
potential limitation of the study is that POM has a
distinct appearance and taste. This was minimized
for the study by taste and color matching the placebo
beverage as well as providing a 2-week washout so
that it would be difficult for subjects to discern any
subtle difference in taste or appearance between the
study beverages. To minimize bias, patients were
asked not to attempt to speculate which month’s
beverage had the active ingredient.
Although the results of this pilot study did not
achieve statistical significance, a trend was demon-
strated toward benefit of erectile function in men
with mild and mild-to-moderate ED based upon
results from self-administered GAQ. Modifying the
design of the study to incorporate a larger cohort of
subjects and longer treatment periods could possi-
bly demonstrate statistical significance. As a power-
ful antioxidant, enhancing the actions of NO in
vascular endothelial cells, POM has great potential
in the management of ED. Of interest would be the
use of this POM in conjunction with medications
that depend heavily on NO activity such as PDE5
Further studies are warranted to clarify
the efficacy and clinical role of POM on male ED.
We thank Karen Edwards for her assistance through-
out this clinical trial. This study was financially sup-
ported by POM Wonderful, LLC.
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protein E-deficient mice. Am J Clin Nutr 2000; 71: 1062–1076.
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Dornfeld L et al. Pomegranate juice consumption for 3 years by
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Efficacy and safety of pomegranate juice
CP Forest et al
International Journal of Impotence Research
... They concluded that PPE significantly reduced the serum levels of total cholesterol and triglycerides in patients with knee OA (Haghighian et al., 2020). Forest et al. (2007) reported that daily consumption of 8 ounces of Pg juice (1.5 mmol of total polyphenols) for 4 weeks improved erectile dysfunction (ED) in male patients with mild-tomoderate ED. This randomized, placebo-controlled, and cross-over design study enrolled 53 volunteers (21-70 years-old) with mild-to-moderate ED. ...
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Pomegranate fruit (Pg) has a long history for promoting health and well-being and curing multiple diseases in many geographic regions of the world. Its large number of bioactive phytochemicals have proven useful in treating chronic non-communicable diseases such as cardiovascular and neurodegenerative disorders, cancer, osteoarthritis, and erectile dysfunction in humans. Punicalagin and ellagic acid are the most abundant biologically active phytochemicals present in Pg. In addition, it containspolyphenols, hydrolysable ellagitannins, gallic acid, and anthocyanins. The cardioprotective, neuroprotective, and anticancer effects of Pg and its components are attributed to the wide range ofstrong antioxidant and antiinflammatory phytochemicals present in Pg fruit, juice, peel, and seeds. Recently, the consumption of Pg fruit and juice has shown steep increasing trends in Western countries. The purpose of this chapter is to summarize the bioactivity of phytoconstituents of Pg, juice, peel, and seeds in health and disease as well as describe the possible pathways through which the bioactive phytochemicals of pomegranate act at the cellular and molecular levels.
... In fact, many types of botanical medicines and natural products are reported to be useful for the prevention and treatment of ED [107,108]. For example, several animal experiments and clinical trials demonstrated that pomegranate juice improved intracavernous blood flow, smooth muscle cell relaxation, and ED symptoms [109][110][111][112]. The reported underlying mechanisms included anti-fibrotic and anti-oxidant activities modulated by NOS, NO, and malondialdehyde (MDA) in the corpus cavernosum [109,111,112]. ...
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Erectile function is regulated by complex mechanisms centered on vascular- and nerve-related systems. Hence, dysregulation of these systems leads to erectile dysfunction (ED), which causes mental distress and decreases the quality of life of patients and their partners. At the molecular level, many factors, such as fibrosis, lipid metabolism abnormalities, the immune system, and stem cells, play crucial roles in the etiology and development of ED. Although phosphodiesterase type 5 (PDE5) inhibitors are currently the standard treatment agents for patients with ED, they are effective only in a subgroup of patients. Therefore, further insight into the pathological mechanism underlying ED is needed to discuss ED treatment strategies. In this review, we focused on the biological and pathological significance of macrophages in ED because the interaction of macrophages with ED-related mechanisms have not been well explored, despite their important roles in vasculogenic and neurogenic diseases. Furthermore, we examined the pathological significance of macrophages in Peyronie’s disease (PD), a cause of ED characterized by penile deformation (visible curvature) during erection and pain. Although microinjury and the subsequent abnormal healing process of the tunica albuginea are known to be important processes in this disease, the detailed etiology and pathophysiology of PD are not fully understood. This is the first review on the pathological role of macrophages in PD.
... Finally, less evidence, conditioned by the small number of studies carried out to date, has been observed in other potential applications upon pomegranate-derived product consumption. For example, daily PJ consumption exerted benefits in 80% of patients (n = 53) with mildmoderate erectile dysfunction (Forest et al., 2007). PE intake also protected against UV-induced pigmentation of human skin (Kasai et al., 2006). ...
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Background The consumption of pomegranate juices and extracts has long been linked to many health benefits beyond nutrition, described mainly by innumerable preclinical studies. However, the European Food Safety Authority (EFSA) concluded in 2010 that a cause and effect relationship could not be established between the consumption of pomegranate-derived products and all the health claims presented. There are no additional EFSA opinions on health claims specifically addressed to pomegranate in the last decade. Scope and approach This review comprehensively compiles all human studies conducted on pomegranate. The aim is to discuss these studies critically to identify possible flaws and propose guidelines that might help establish a cause and effect relationship between pomegranate-derived product consumption and health. Key findings and conclusions To date, 86 human studies have evaluated the health benefits of pomegranate juices and extracts. The most promising, albeit scarce, evidence is related to blood pressure improvement. Less evidence deals with inflammation, cancer, cognitive function, physical activity, and gut microbiota modulation (prebiotic effects). After a decade since EFSA's opinion, human evidence remains inconsistent, making it difficult to support most claimed health effects. The lack of effects and(or) data discrepancy might be attributable to design limitations, including insufficient product characterization and interindividual variability that influence pomegranate polyphenols' bioefficacy. New coordinated strategies between policy makers, research/academic institutions, and industry are needed to move forward. Therefore, this review presents a roadmap to conduct well-designed trials and cover existing gaps, which could establish a cause-effect relation between pomegranate consumption and health benefits beyond nutrition.
... Nephroprotection [93] Mutraghata (urinary retention) 4 Inflammatory diseases Amavata (rheumatism due to ama) 3 Antiarthritic activity [94] Anti-inflammatory [95] Analgesic activity [96] Vatarakta (gout) 2 Vatavyadhi (disorder due to vata) 14 Bhagashotha (inflammation of female genital) 2 Shoola (colic pain) 21 Garbhashoola (pain due to fetus) 1 Oral diseases Dantaroga (tooth disorder) 5 Dental plaque microorganism [97] Mukharoga (oral cavity disorder) 2 Gynecological diseases Sutika roga (puerperial disorder) 3 Uterine contractile activity [98] Bandhyatva (female infertility) 2 Estrogenic activity [99] Male reproductive diseases Lingavridhhikar (penis enhancer) 2 Erectile dysfunction activity [100] Vajikarana (aphrodisiac) 8 Spermprotective activity [101] Other diseases Vrana (wound) 2 Wound healing activity [102] Prameha (diabetes) 10 Antidiabetic with hyperlipidemia [103][104][105] Medoroga (obesity) 2 Antiobesity activity [106] Jvara (fever) 11 Antimalarial activity [107] Krimi (worm ) 6 Anthelmintic [108] Shramahara (anti-fatigue) 1 Ergogenic activity [109] Rasayana (rejuvenation) 1 Immunomodulatory activity [110] Amlapitta (hyperacidity) 3 Antiulcerative activity [111] Tvaka Vaivarnyata (skin discoloration) 3 ...
... Both group experienced nausea and diarrhea [176]. The safety and tolerability of short-term or longtern consumption of pomegranate juice or extract have been confirmed by other investigators [178,179,[197][198][199]. Heber et. ...
Cancer remains to be the second highest cause of mortality in our society, falling just short of heart disease. Despite major advancement in cancer therapy over the past decade, momentum has been gaining for an alternative approach of using naturally-occurring and dietary agents for cancer prevention and management. Research on pomegranate (Punica granatum L.), a fruit of the Punicaceae family, has shown enormous potential for cancer prevention and intervention. In addition to a rich source of polyphenols, including flavonoids and ellagitannins, in its juice, pomegranate also houses hundreds of other phytochemicals in its pericarp, seed, flower, bark, flowers and leaves, These phytochemicals provide powerful antiproliferative, anti-inflammatory, antioxidant, anti-invasive, antimigratory, anti-angiogenic and anti-metastatic effects without significant toxicity. This makes the use of its various extracts a very attractive strategy to our current battle against cancer. This review article presents a systematic, comprehensive and critical review of research on pomegranate-derived products in both cancer prevention and intervention. It discusses the chemical constituents of pomegranate, the results of both preclinical (in vitro, ex vivo and in vivo) and clinical studies on the anticancer effect of pomegranate phytochemicals and molecular targets in numerous types of cancers, such as breast, gastrointestinal tract (oral, colon, liver and pancreas), gynecological (uterine and ovarian), hematological (lymphoma, leukemia and myeloma), lung, neurological (glioma), urogenital (bladder and prostate), bioavailability, pharmacokinetics and safety of pomegranate constituents. In order to guide the direction of future research, we have also included current limitations and challenges in the field and our post analysis recommendation.
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Punica granatum L. belongs to the Punicaceae family which is distributed around the world. Different parts of pomegranate like seed, peel, juice, and leaves are rich in potential bioactive compounds. These plants have found application in traditional medicine such as in treatment of gastrointestinal, cardiovascular, and endocrine diseases, among others. The present review aimed to summarize the current research on the traditional and scientific applications of P. granatum with regard to the phytochemical content and clinical applications that may be useful for future drug development. Information about P. granatum was obtained from local classic herbal literature and electronic databases, such as PubMed, Scopus, and ScienceDirect. Several phytochemical constituents including polyphenolics, flavonoids, anthocyanosides, alkaloids, lignans, and triterpenes have been reported from the plant. Randomized clinical trials have provided evidence as to the pharmacological activities of pomegranate in several diseases including diabetes, cardiovascular disease, oral cavity disorders, endocrine disorders, and cancer. The present review has provided an insight into the traditional applications of the plants, and some of them have been validated by scientific evidence, particularly their applications as treatment of cardiovascular and endocrine diseases.
Erectile dysfunction (ED) is defined as an inability to achieve or maintain penile erection sufficiently enough for sexual performance. Sexual function involves an interplay between psychological, vascular, neurological, endocrine functions; thus the various etiologies of ED can be divided into psychosocial or organic causes. Current mainstays of treatment for ED are centered around enhancing levels of nitric oxide at the nerve terminal with pharmacologic agents such as phosphodiesterase inhibitors, followed by more invasive therapies such as intracavernosal injections and penile prosthesis. The market for supplements for ED has been growing in popularity and has warranted further investigation into mechanisms of action and efficacy. This chapter discusses several supplements that have been marketed as therapies for ED, their efficacies in clinical trials, as well as their mechanism of action on the biochemical level, safety profiles, and adverse effects.
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Objectives: To systematically review and discuss the current evidence from placebo-controlled clinical trials that investigated the use of alternative medicines and herbal remedies in the management of erectile dysfunction (ED). Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based systematic review using specific keyword combinations was conducted on the PubMed and Scopus databases. Randomised controlled trials investigating herbal medicine in at least one group and using the International Index of Erectile Function (IIEF) as an outcome in patients primarily diagnosed with ED were included for review. Results: Following the literature search, screening and eligibility analysis, a total of 42 articles were included. The 42 articles were categorised as single herb extractions (n = 14), combination herbal formula (n = 5), combination of herbal formula and non-herbal nutraceuticals (n = 7), non-herbal nutraceuticals (n = 5), acupuncture and moxibustion (n = 2), diet and nutrition (n = 3), exercise (n = 5), and topical treatments (n = 1). Based on the results, Korean ginseng, Pygnogenol and Prelox, Tribulus terrestris, Lepidium meyenii, L-arginine, acupuncture and lifestyle interventions were the more predominantly investigated treatments interventions for ED. Conclusions: Panax ginseng, Pygnogenol, Prelox and Tribulus terrestris have promising evidence as herbal products, alongside L-arginine as a nutritional supplement, for ED based on IIEF outcomes, and warrant further clinical investigation. The mechanisms of action remain unclear, but each of these appears to in part increase nitric oxide synthesis. Importantly, improved diet and exercise should be considered, particularly in patients with obesity or diabetes mellitus.
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The custom of using plants for the therapeutic and dietary practices is as old as origin of humanity on the earth. One of the most ancient fruit plant is Punica granatum L., pomegranate belongs to Lythraceae family. The plant has a very rich ethnic history of its utilization around the world. The plant was used to symbolize prosperity, life, happiness, fertility etc. Apart from the ethnic beliefs associated with the plant, it is a well-considered plant based remedy used in treatment of many diseases in traditional system like Ayurveda and folk system of medicine. In Ayurveda it is esteemed as a Rasayana. It is used in many Ayurvedic polyherbal formulations which are used against many diseases. The plant consists of numerous phytochemical constituents in it such as polysaccharides, minerals, polyphenols, tannins, saponins, quinones, alkaloids, glycosides, coumarins, terpenoids, steroids etc. Each of the phytochemical constituent is associated with important therapeutic properties. This supper food is globally known for its high anti-oxidant potential. Other associated properties of this medicinal fruit plant are anti-microbial, hepatoprotective, cardioprotective, anti-diabetic, anti-cancer, immunomodulatory, anti-inflammatory, anti-hypertensive, anti-anemic etc. The aim of present review is to provide information related to phytochemistry, traditional uses in Ayurveda and folk medicinal system and therapeutic properties of Punica granatum L. Keywords: Dadim, Rasapanchak, Punicalagin, Punicic acid, Anti-oxidant.
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Dietary supplementation with nutrients rich in antioxidants is associated with inhibition of atherogenic modifications to LDL, macrophage foam cell formation, and atherosclerosis. Pomegranates are a source of polyphenols and other antioxidants. We analyzed, in healthy male volunteers and in atherosclerotic apolipoprotein E-deficient (E(0)) mice, the effect of pomegranate juice consumption on lipoprotein oxidation, aggregation, and retention; macrophage atherogenicity; platelet aggregation; and atherosclerosis. Potent antioxidative effects of pomegranate juice against lipid peroxidation in whole plasma and in isolated lipoproteins (HDL and LDL) were assessed in humans and in E(0) mice after pomegranate juice consumption for </=2 and 14 wk, respectively. In humans, pomegranate juice consumption decreased LDL susceptibility to aggregation and retention and increased the activity of serum paraoxonase (an HDL-associated esterase that can protect against lipid peroxidation) by 20%. In E(0) mice, oxidation of LDL by peritoneal macrophages was reduced by up to 90% after pomegranate juice consumption and this effect was associated with reduced cellular lipid peroxidation and superoxide release. The uptake of oxidized LDL and native LDL by mouse peritoneal macrophages obtained after pomegranate juice administration was reduced by 20%. Finally, pomegranate juice supplementation of E(0) mice reduced the size of their atherosclerotic lesions by 44% and also the number of foam cells compared with control E(0) mice supplemented with water. Pomegranate juice had potent antiatherogenic effects in healthy humans and in atherosclerotic mice that may be attributable to its antioxidative properties.
To develop a brief, reliable, self-administered measure of erectile function that is cross-culturally valid and psychometrically sound, with the sensitivity and specificity for detecting treatment-related changes in patients with erectile dysfunction. Relevant domains of sexual function across various cultures were identified via a literature search of existing questionnaires and interviews of male patients with erectile dysfunction and of their partners. An initial questionnaire was administered to patients with erectile dysfunction, with results reviewed by an international panel of experts. Following linguistic validation in 10 languages, the final 15-item questionnaire, the international index of Erectile Function (IIEF), was examined for sensitivity, specificity, reliability (internal consistency and test-retest repeatability), and construct (concurrent, convergent, and discriminant) validity. A principal components analysis identified five factors (that is, erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) with eigenvalues greater than 1.0. A high degree of internal consistency was observed for each of the five domains and for the total scale (Cronbach's alpha values of 0.73 and higher and 0.91 and higher, respectively) in the populations studied. Test-retest repeatability correlation coefficients for the five domain scores were highly significant. The IIEF demonstrated adequate construct validity, and all five domains showed a high degree of sensitivity and specificity to the effects of treatment. Significant (P values = 0.0001) changes between baseline and post-treatment scores were observed across all five domains in the treatment responder cohort, but not in the treatment nonresponder cohort. The IIEF addresses the relevant domains of male sexual function (that is, erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), is psychometrically sound, and has been linguistically validated in 10 languages. This questionnaire is readily self-administered in research or clinical settings. The IIEF demonstrates the sensitivity and specificity for detecting treatment-related changes in patients with erectile dysfunction.
To evaluate the erectile function (EF) domain of the International Index of Erectile Function (IIEF) as a diagnostic tool to discriminate between men with and without erectile dysfunction (ED) and to develop a clinically meaningful gradient of severity for ED. One thousand one hundred fifty-one men (1035 with and 116 without ED) who reported attempting sexual activity were evaluated using data from four clinical trials of sildenafil citrate (Viagra) and two control samples. The statistical program Classification and Regression Trees was used to determine optimal cutoff scores on the EF domain (range 6 to 30) to distinguish between men with and without ED and to determine levels of ED severity on the EF domain using the IIEF item on sexual intercourse satisfaction. For a 0.5 prevalence rate of ED, the optimal cutoff score was 25, with men scoring less than or equal to 25 classified as having ED and those scoring above 25 as not having ED (sensitivity 0.97, specificity 0.88). Sensitivity analyses revealed a robust statistical solution that was well supported with different assumed prevalence rates and several cross-validations. The severity of ED was classified into five categories: no ED (EF score 26 to 30), mild (EF score 22 to 25), mild to moderate (EF score 17 to 21), moderate (EF score 11 to 16), and severe (EF score 6 to 10). Substantial agreement was shown between these predicted and "true" classes (weighted kappa 0.80). The EF domain possesses favorable statistical properties as a diagnostic tool, not only in distinguishing between men with and without ED, but also in classifying levels of ED severity. Clinical validation with self-rated assessments of ED severity is warranted.
The goal of this study was to determine whether patients with vascular erectile dysfunction (ED) and no other clinical cardiovascular disease have structural and functional abnormalities of other vascular beds. In many ED patients, vascular disease is the major underlying cause. It may be that ED is an early marker of atherosclerosis in patients without clinical cardiovascular disease. We assessed systemic vascular structure and function in 30 patients with ED and 27 age-matched normal control (NL) subjects. We measured vascular parameters, including: 1) carotid and brachial artery diameters, intima-media thickness, compliance, and distensibility; 2) aortic pulse wave velocity; 3) coronary calcification; and 4) brachial artery endothelium-dependent and -independent vasodilation. There were no significant differences in baseline demographics, coronary artery risk score, or lipid values between the two groups. Most structural and functional vascular parameters were similar in the ED and NL groups. Brachial artery flow-mediated vasodilation (FMD) (1.3 vs. 2.4%, p = 0.014) and vasodilation to nitroglycerin (NTG) (13.0 vs. 17.8%, p < 0.05) were significantly reduced in ED patients, compared with NL subjects. In addition, there was a significant correlation between FMD and vasodilation to NTG in ED patients (r = 0.59, p < 0.05) but not in NL subjects. Patients with ED but no clinical cardiovascular disease have a peripheral vascular defect in endothelium-dependent and -independent vasodilation that occurs before the development of other overt functional or structural systemic vascular disease and is independent of other traditional cardiovascular risk factors.
Dietary supplementation with polyphenolic antioxidants to animals was shown to be associated with inhibition of LDL oxidation and macrophage foam cell formation, and attenuation of atherosclerosis development. We investigated the effects of pomegranate juice (PJ, which contains potent tannins and anthocyanins) consumption by atherosclerotic patients with carotid artery stenosis (CAS) on the progression of carotid lesions and changes in oxidative stress and blood pressure. Ten patients were supplemented with PJ for 1 year and five of them continued for up to 3 years. Blood samples were collected before treatment and during PJ consumption. In the control group that did not consume PJ, common carotid intima-media thickness (IMT) increased by 9% during 1 year, whereas, PJ consumption resulted in a significant IMT reduction, by up to 30%, after 1 year. The patients' serum paraoxonase 1 (PON 1) activity was increased by 83%, whereas serum LDL basal oxidative state and LDL susceptibility to copper ion-induced oxidation were both significantly reduced, by 90% and 59%, respectively, after 12 months of PJ consumption, compared to values obtained before PJ consumption. Furthermore, serum levels of antibodies against oxidized LDL were decreased by 19%, and in parallel serum total antioxidant status (TAS) was increased by 130% after 1 year of PJ consumption. Systolic blood pressure was reduced after 1 year of PJ consumption by 12% [corrected] and was not further reduced along 3 years of PJ consumption. For all studied parameters, the maximal effects were observed after 1 year of PJ consumption. Further consumption of PJ, for up to 3 years, had no additional beneficial effects on IMT and serum PON1 activity, whereas serum lipid peroxidation was further reduced by up to 16% after 3 years of PJ consumption. The results of the present study thus suggest that PJ consumption by patients with CAS decreases carotid IMT and systolic blood pressure and these effects could be related to the potent antioxidant characteristics of PJ polyphenols.
We searched for markers of oxidative stress in cavernous ischemia and examined the effect of long-term antioxidant intake on arteriogenic erectile dysfunction (ED) in the rabbit. Antioxidant activity of known antioxidant beverages, such as pomegranate juice (PJ), red wine, blueberry juice, cranberry juice, orange juice and green tea, was examined spectrophotometrically. PJ demonstrated the highest free radical scavenging capacity. The effect of long-term PJ intake on intracavernous blood flow and penile erection was then examined in the rabbit model. Erectile tissues were processed to assess oxidative stress and smooth muscle relaxation, immunohistochemical staining of nitric oxide synthase (NOS) and histomorphometry. On spectrophotometric analysis PJ showed the highest capacity to decrease low density lipoprotein oxidation and inhibit cellular oxidative stress in macrophages. The rabbit model of arteriogenic ED demonstrated decreased intracavernous blood flow, erectile dysfunction, loss of smooth muscle relaxation, decreased endothelial NOS and neuronal NOS, increased inducible NOS expression, diffused cavernous fibrosis and increased cavernous levels of the oxidative product isoprostane 8-epi-prostaglandin F2alpha. Long-term PJ intake increased intracavernous blood flow, improved erectile response and smooth muscle relaxation in ED and control groups while having no significant effect on NOS expression. PJ intake prevented erectile tissue fibrosis in the ED group. Arteriogenic ED accumulates oxidative products in erectile tissue, possibly via an intrinsic mechanism. Oxidative stress may be of great importance in the pathophysiology of arteriogenic ED. Antioxidant therapy may be a useful prophylactic tool for preventing smooth muscle dysfunction and fibrosis in ED.
Evidence exists that erectile dysfunction (ED) is analogous to endothelial dysfunction, a known precursor to atherosclerosis in terms of molecular mechanisms and underlying risk factors. These findings are discussed, along with the biologic underpinnings for the clinical observation that ED is an "early warning system" for atherosclerosis. Molecular mechanisms of ED as potential targets of novel therapies are considered, as well as the role of phosphodiesterase 5 inhibitors--currently the most effective treatment of ED--as promising therapies of cardiovascular diseases characterized by endothelial dysfunction.
Pomegranate juice (PJ), which is a rich source of potent flavonoid antioxidants, was tested for its capacity to protect nitric oxide (NO) against oxidative destruction and enhance the biological actions of NO. Employing chemiluminescence headspace analysis, PJ was found to be a potent inhibitor of superoxide anion-mediated disappearance of NO. PJ was much more potent than Concord grape juice, blueberry juice, red wine, ascorbic acid, and DL-alpha-tocopherol. As little as 3 microl of a 6-fold dilution of PJ, in a reaction volume of 5000 microl, produced a marked antioxidant effect, whereas 300 microl of undiluted blueberry juice or nearly 1000 microl of undiluted Concord grape juice were required to produce similar effects. PJ and other antioxidant-containing products were found to augment the anti-proliferative action of NO (DETA/NO) on vascular smooth muscle cell (rat aorta) proliferation. PJ was much more effective than the other products tested and elicited no effects when tested alone in the absence of added NO. Similarly, neither PJ nor the other products enhanced the anti-proliferative action of alpha-difluoromethylornithine, a stable substance that inhibits cell growth by NO-independent mechanisms. In order to determine whether PJ is capable of increasing the production of NO by vascular endothelial cells, PJ was tested for its capacity to upregulate and/or activate endothelial NO synthase (eNOS) in bovine pulmonary artery endothelial cells. PJ elicited no effects on eNOS protein expression or catalytic activity. Moreover, PJ did not enhance promoter activity in the eNOS gene (COS-7 cells transfected with eNOS). These observations indicate that PJ possesses potent antioxidant activity that results in marked protection of NO against oxidative destruction, thereby resulting in augmentation of the biological actions of NO.
Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. Review
  • A Agarwal
  • Kc Nandipati
  • Rk Sharma
  • Cd Zippe
Agarwal A, Nandipati KC, Sharma RK, Zippe CD, Raina R. Role of oxidative stress in the pathophysiological mechanism of erectile dysfunction. Review. J Androl 2006; 27: 335–347.