Lycopene Inhibits Disease Progression in Patients with Benign Prostate Hyperplasia Study Presented By: Kelly Skretta OHSU Dietetic Intern April 2008

Authors & Citation 

Authors      

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Silke Schwartz Ute C. Obermuller-Jevic Eva Hellmis Winfried Koch Gunther Jacobi Han-Konrad Biesalski

Citation 

Journal of Nutrition, 138(1): 49-53. Jan 2008.

Study Institutions (Germany) 

University of Hohenheim 

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Institute of Biological Chemistry & Nutrition

BASF Aktiengesellschaft Urologic-Andrologic Medical Practice HaaPACS GmbH

Background of Lycopene1 

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1

A carotenoid: gives red color to tomatoes, guava, rosehip, watermelon and pink grapefruit An antioxidant: neutralizes free radials Deposited in the liver, lungs, prostate gland, colon and skin Concentration in body tissues tends to be higher than all other carotenoids Source: http://www.lycopene.org/

Background of Benign Prostate Hyperplasia (BPH) 

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Enlarging prostate due to more rapid reproduction of cells in central region Risk factor for developing prostate cancer (PCa) Common disease of elderly men Affects ~50% of men in their 50s; ~90% men in their 80s and older Clinical symptoms reported in ~25% and ~50% of men in these age groups

Study Justification 

Studies on lycopene & prostate cancer (PCa) have shown promise 

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Epidemiological: regular intake and high blood levels of lycopene associated with reduced risk of PCa Experimental: lycopene inhibits prostate tumor growth progression & PCa cell proliferation

Clinical studies have been limited to patients with PCa

Study Justification cont. 

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Chemopreventative potential of lycopene needs to be explored in men Preventative role suggested in previous studies: 

Lycopene possibly has a beneficial role in patients with benign prostate hyperplasia (BPH) who are at elevated risk of PCa

Aim of this Study 

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Investigate whether intake of lycopene supplements inhibits disease progression in patients with BPH, improving clinical diagnostic markers and symptoms of BPH Randomized clinical pilot study

Study Subjects 

Eligibility Criteria: 

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Serum prostatespecific antigen (PSA) concentration >4.0 µg/L Confirmed BPH Between 45-70 years old men Absence of acute illness

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Exclusion Criteria examples: 

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Proven PCa or other malignancies Chronic diseases of liver/kidney Ongoing drug therapy for BPH or taking substances that affect hormone status

Study Subjects cont. 

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327 patients screened (October 2004 – July 2005) 49 met criteria 40 elected to participate

Study Design 

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Randomized, double-blind, placebocontrolled Patients randomly received either 15 mg/dose lycopene or placebo for 6 mo. 

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15mg daily dose based on previous bioavailability study

Subjects instructed to take 1 capsule/day with lunch

Study Protocol Table 1 Study Protocol: Biochemical Variables, Clinical Examinations, & Nutritional Assessment (Schedule)

Screening

Biochemical parameters1

Clinical Examinations

Nutritional assessment

PSA (total)

Biopsy (prostate)

Lycopene (plasma)

IGF-1, IGF-BP-3, testosterone, LDL cholesterol, Baseline (Visit 1) total cholesterol, glucose, hemogram

Lycopene (prostate) DRE, TRUS IPSS questionnaire

After 1 mo (Visit 2) PSA

IPSS questionnaire

After 3 mo (Visit 3) PSA

IPSS questionnaire

PSA, IGF-1, IGF-BP-3, testosterone, LDL cholesterol, total cholesterol, glucose, hemogram After 6 mo (Visit 4) (whole blood) DRE, TRUS IPSS questionnaire 1Analyzed

in serum unless otherwise indicated.

Lycopene (plasma) Lycopene (BMC) Dietary protocol Lycopene (plasma) Dietary protocol Lycopene (plasma) Dietary protocol

Lycopene (plasma) Lycopene (BMC) Dietary protocol

Clinical Exams   

Fasting blood samples from antecubital vein BMC collected using the PASCOE multivitamin test DRE: digital rectal examination 

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Determined prostate size

TRUS: trans-rectal ultrasonography  Guided biopsies of 3 tissues samples each of R & L prostate lobes  Determined prostate weight IPSS questionnaire: International Prostate Symptom Score  Measured clinical symptoms & QOL index

During Intervention 

Not allowed:  

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Patients advised not to change dietary habits 

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Adjuvant BPH therapy Intake of self-selected dietary supplements

Monitored by FFQ that was modified to assess foods rich in lycopene

A compliance check at each visit

Statistical Analysis 

Linear model 

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Change of total PSA from baseline to visit 4

Planned comparisons within and between groups due to low statistical power 

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Within groups: Wilcoxon’s Signed-Rank Test Two-sided = 0.05 P<0.1 considered statistical tendencies

Results 

Adherence: 

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19 subjects completed study in lycopene group (out of 20) 18 subjects in placebo group completed study (out of 20)

Anthropometric, Dietary, & Serum Biochemical Characteristics Table 2 Anthropometric, Dietary, & Serum Biochemical Characteristics of BPH Patients at Baseline & After 6 Months of Lycopene Supplementation1 Placebo Characteristic n Age, y

Baseline 18

Lycopene

6 mo

Baseline 18

19

6 mo 19

Height, m

67.7 ± 5.6 (69.0) 1.74 ± 0.06 (1.74)

Weight, kg

79.9 ± 8.8 (81.0) 78.6 ± 8.5 (80.5) 84.7 ± 9.7 (86.0) 84.6 ± 9.4 (84.5)

BMI, kg/m2

26.3 ± 2.0 (27.0) 25.9 ± 2.1 (25.8) 27.0 ± 2.0 (26.7) 27.0 ± 1.8 (26.9)

Energy intake, MJ/d

11.6 ± 4.3 (10.5) 9.3 ± 3.4* (8.8) 12.4 ± 3.0 (13.0) 11.4 ± 2.9 (11.2)

Dietary lycopene intake, mg/d 6.2 ± 11.5 (4.1) 6.1 ± 6.6 (4.0) Glucose, mmol/L 5.8 ± 1.1 (5.4) 6.0 ± 1.1 (5.5)

67.0 ± 4.6 (67.0) 1.77 ± 0.07 (1.78)

6.2 ± 5.9 (3.8) 9.2 ± 15.5 (4.2) 6.4 ± 1.6 (5.9) 5.9 ± 1.1 (5.4)

Total cholesterol, mmol/L

6.0 ± 1.3 (6.2) 5.4 ± 1.1** (5.5) 5.4 ± 0.9 (5.3)

5.3 ± 0.8 (5.3)

LDL cholesterol, mmol/L

4.0 ± 1.1 (3.9) 3.5 ± 1.1** (3.5) 3.3 ± 0.9 (3.3)

3.3 ± 0.7 (3.3)

Total testosterone, nmol/L

16.7 ± 5.6 (14.6) 16.7 ± 4.9 (16.3) 16.3 ± 4.9 (16.7) 16.7 ± 5.2 (17.0) 47.9 ± 14.6 43.7 ± 14.2 39.9 ± 10.8 39.2 ± 10.4 Free testosterone, pmol/L (46.2) (43.7) (41.0) (38.2) 1Values are means ± SD (median). Asterisks indicate different from baseline: *P<0.05, **P<0.01 (Wilcoxon Signed-Rank Test).

Serum PSA, IGF-1, IGF-BP-3, & Lycopene Status TABLE 3 Serum PSA, IGF-1, IGF-BP-3, and Lycopene Status in BPH Patients at Baseline and After 6 mo of Lycopene Supplementation1 Placebo

n Primary endpoints Serum total PSA,2 µg/L Serum free PSA, µg/L Secondary endpoints Plasma lycopene, µmol/L Prostate lycopene, µmol/g BMC lycopene, pmol/µg DNA Serum IGF-1, nmol/L

Lycopene

Baseline 18

6 mo 18

Baseline 19

6 mo 19

6.85 ± 2.3 (6.31)

6.81 ± 4.7 (5.07)

6.56 ± 2.3 (5.87)

5.82 ± 1.8* (5.57)

—

0.98 ± 0.53 (0.87)

—

0.93 ± 0.33 (0.85)

0.46 ± 0.24 (0.38) 0.54 ± 0.25 (0.60) 0.43 ± 0.22 (0.42) 0.45 ± 0.25 (0.43)

—

0.51 ± 0.30 (0.43)

1.24 ± 0.31**,## (1.23) —

0.06 ± 0.07 (0.05) 0.17 ± 0.14* (0.11) 0.06 ± 0.1 (0.00) 0.59 ± 0.58**,# (0.38) 20.8 ± 7.1(20.5) 19.5 ± 7.5 (19.2) 21.3 ± 8.0 (21.5) 21.4 ± 6.7 (20.9) 156.5 ± 34.8 146.1 ± 34.8 170.4 ± 41.7 Serum IGF-BP-3, nmol/L (153.0) (146.1) (166.9) 166.9 ± 27.8 (166.9) 1 Values are means ± SD (median). Asterisks indicate different from baseline, * P < 0.05, ** P < 0.0001 (Wilcoxon Signed-Rank Test). #, Change from baseline different from placebo group, # P < 0.01, ## P < 0.0001 (linear model with age, BMI, and plasma lycopene at baseline as covariates). 2

Total PSA determined during screening instead of baseline (explanation in Subjects and Methods).

Results of Clinical Exams & IPSS TABLE 4 Results from Clinical Examinations and IPSS in BPH Patients at Baseline and After 6 mo of Lycopene Supplementation1 Placebo

Lycopene

Baseline 18

6 mo 18

Baseline 19

6 mo 19

DRE, mL

43.6 ± 12.1 (40.0)

55.3 ± 25.6** (50.0)

47.4 ± 15.2 (40.0)

49.7 ± 13.0 (50.0)

TRUS, g

40.5 ± 13.0 (36.9)

50.1 ± 21.1* (46.5)

42.2 ± 14.3 (37.0)

43.4 ± 11.9 (43.0)

12.4 ± 2.0 (12.5)

10.1 ± 4.8* (9.5)

7.3 ± 0.9 (7.0) 5.2 ± 1.5 (5.0) 1.8 ± 0.7 (2.0)

5.6 ± 3.1* (5.0) 4.5 ± 2.2 (4.0) 2.2 ± 1.0 (2.0)

n

IPSS, points IPSS obstruction-related,2 points IPSS irritation-related,3 points IPSS quality of life, points 1Values

12.0 ± 2.4 (12.0) 10.3 ± 4.0** (10.0) 7.2 ± 1.6 (7.0) 4.8 ± 1.1 (4.0) 2.1 ± 0.6 (2.0)

5.9 ± 2.9** (6.0) 4.4 ± 1.5 (4.0) 2.1 ± 0.8 (2.0)

are means ± SD (median). Asterisks indicate different from baseline:*P<0.05, **P<0.01 (Wilcoxon Signed-Rank Test).

2

Includes IPSS question nos. 1,3,5, & 6.

3Includes

IPSS question nos. 2,4, & 7.

FIGURE 1 Changes in serum total PSA (A), DRE (B), and TRUS (C) in BPH patients supplemented with lycopene or placebo for 6 mo adjusted to relevant baseline covariates

Schwarz, S. et al. J. Nutr. 2008;138:49-53

Copyright ©2008 American Society for Nutrition

Discussion 

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Primary aim of study (to inhibit PSA increase in blood through lycopene intake) was achieved within 6-mo study period Favorable effect of lycopene in BPH patients confirmed by: 

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Clinical diagnostic markers for disease progression based on within-group comparisons

Lycopene supplementation was well tolerated by participants

Discussion cont. 

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Older BPH patients had smaller increases in plasma lycopene concentrations and higher increases in BMC concentrations Obesity (BMI >30kg/m2) was associated with increased disease progression (shown by DRE, TRUS) Lack of effect of lycopene on IGF-1 & IGF-BP3 plasma levels was unexpected 

Lycopene is known to modulate IFG-1 signaling in experimental studies

Conclusions 

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Lycopene at 15mg/day for 6 months may inhibit disease progression & may lessen symptoms in BPH patients Analysis of lycopene in BMC:  

May be suitable for routine screening May serve as basis for recommending supplementation in long-term management of prostate health

Lycopene Supplement & Dietary Amounts 

Consumption of 15mg/day of lycopene from dietary supplements & diet seems feasible for elderly men in long term

Lycopene in Certain Foods Food

Amount

Canned Tomato Sauce 1 cup Canned Tomato Juice 1 cup Canned Pasta with Meatballs in Tomato Sauce 1 cup Canned Tomato Soup 1 cup Raw Watermelon 1 wedge Catsup 1 tbsp Raw Grapefruit 1/2 piece Cooked Asparagus 4 spears Raw Carrot 1 cup

Lycopene Content (mg) 37.122 21.96

19.326 13.042 12.962 2.506 1.745 0.018 0.001

*Source: USDA National Nutrient Database for Standard Reference, Release 20. http://www.ars.usda.gov/Main/docs.htm?docid=15869

Critique of Article 

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Criticisms  Pilot study of small sample size/low power  No biopsy at visit 4 Application to dietetic practice  Provides more strength to base our patient education of lycopene preventative benefits Further research is needed  Larger sample sizes; focus on chemoprevention

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