Serum Estrogens in Men

Hyperestrogenemia Total

&
Testosterone
7000
7000
6000 Progesterone
Serum
Prostate Hormone
Levels
5000

4000
in men =
Progesterone
in women
Mela-
tonin
(follicular
Hypertrophy in Men 3000

2000
phase)
DHT E1 E2
(at
night) Free
T4
1000 40 25 100 2.5
1000
700
0

Progesterone is an abundant hormone in men

Thierry Hertoghe, MD

Prostate Examination

Prostate
hypertrophy

AGE PROSTATE VOLUME

50 Benign Prostatic Hypertrophy
40 Bone scintigram (anterior view) shows
30 superior displacement of the bladder.
20 esp. of transitional
zone, less of peripheral
10 zones
0
20 40 50 60 70 80

Figure : the total prostate volume increases with age

(Meikle AW et al, J Clin Endoc Metab, 1997, 82: 571-575)

1
 Annual growth rate of prostate
Prostate Cancer
Prostate. 1994 Jun;24(6):279-84. Natural course of human benign prostatic
hyperplasia with relation to urinarydisturbance.Kitagawa N, Ichikawa T, Akimoto
S, Shimazaki J.Department of Urology, School of Medicine, Chiba University,
Japan.To examine the natural course of human benign prostatic hyperplasia
(BPH), casesin health care examination with or without slight urinary symptoms
were examinedby echography. In comparison with these cases, the size of the
prostate wasexamined in patients who received prostatectomy. Prostatic sizes of
health carecases varied widely along with increasing age, but could be divided
into twogroups: increasing or no-change. According to serial determinations of
prostaticsizes in the increasing group, the annual growth rate of the prostate
wascalculated as 1.65 +/- 1.13 and 0.85 +/- 0.44 g in men < 65 years old and in
men> or = 65 years old, respectively. Distribution of prostatic sizes as a functionof
age in health care cases was similar to that in operated patients, showingthat the
size was not correlated with urinary symptoms or surgical indication.Since
uroflow rates decreased along with increasing age in the no-change groupof
operated patients, aging was a factor in deterioration of uroflow. Betweenthe
increasing and the no-change groups in health care cases, differences werefound
in total cholesterol and neutral fat in serum, in addition togamma-seminoprotein;
the latter may be due to differences in the size of theprostate. In conclusion,
natural course of the prostatic hyperplasia isseparated into two groups,
increasing and no-change. Occurrence of urinarysymptoms does not simply
relate to an increase in prostatic weight but, at leastin part, to the aging process.

PERIPHERAL METABOLISM OF
PLASMA TESTOSTERONE
Plasma testosterone
Prostate cancer: 5 mg/day

is estrogen Aromatase 5 -reductase

17 -OH-steroid Hydroxylases
dehydrogenase conjugating enzymes
excess the 0,3 % 6-8%
40 % 50 %

hormonal Plasma dihydro- 17 ketosteroids-

Polar metabolites
Plasma estradiol androstene & diols, triols &
pathogenic factor? 0,02 mg/day
testosterone
0,3 mg/day
etiocholanolone
2 mg/day
conjugates
2,5 mg/day
active excretory
metabolites metabolites
(from Griffin JE, Wilson JD. The testis in Bondy PK, Rosenberg CE, eds. Metabolic
Control & disease. 8th ed. Philadelphia: WB Saunders 1986: 1535-1578)

ANDROGEN - ESTROGEN
DYNAMICS IN MEN
Androstenedione Testosterone
Human
3000 g/day

Peripheral
Adipose tissue
1,6 %
6000 g/day
Adipose tissue
0,31 %
Studies:
17 g Peripheral

Observational
formation 45 g
testes 22 g formation
21 g
93 % 49 % 6 g testes

estrone : 66 g/day 17 -estradiol : 45 g/day

Figure : androgen-estrogen dynamics in 4 normal men. Thus estradiol

arises from plasma testosterone, from estrone derives from
androstenedione & from direct secretion by the testes
(Mac Donald PC et al, J Clin Endocrinol Metab, 1979, 49: 905-916)

2
 Age => increasingly E2:testo ratio
Men
Serum bioavailable testosterone
Mean

Age =>
60 53.8 P = 0.001 -30 %
serum 50.2
0.50
bioavailable
41.2
testosterone 0.42 0.44
-30 %
Serum estradiol / bioavailable testosterone ratio
(ng/dL)
P = 0.04
0

Age
< 60 60-69 > 69 yrs

the serum E2 level Figure: Bioavailable testosterone levels declined with increasing cross-sect. age
from 53.8, 50.2, to 41.2 ng/dl (P = 0.001) in men aged <60, 60-69, & >69 years
Among men w/ bioav. Testo > median, estradiol levels had a dose response ass. w/
prostate size. Among men + bioav. Testo </= the median => no assoc.
n = 32 men; median age, 60.9 years; follow-up for 12 years
Roberts RO, Jacobson DJ, Rhodes T, Klee GG, Leiber MM, Jacobsen SJ. Serum sex hormones and
measures of benign prostatic hyperplasia. Prostate. 2004 Oct 1;61(2):124-31.
Mayo Clinic College of Medicine, Rochester, Minnesota

STEROID RATIO IN AGING MALE

TESTOSTERONE
ESTRADIOL Other

Prostate Stroma Cell proliferation is stimulated by

Factors =>
an increasing ratio of estrogen:androgen.

King KJ,Nicholson HD, Assinder SJ. Effect of increasing ratio of estrogen: androgen on proliferation of
normal human prostate stromal and epithelial cells, and the malignant cell line LNCaP.
the serum E2 level
Prostate. 2006 Jan 1;66(1):105-14.

BMI => prostate volume

n = 50 men without prostate cancer

Prostate Volume - BMI was correlated positively with prostate

volume (p < 0.01)
- positive rates of estrogen receptors showed no
Overweight => bigger sign. difference between the 2 groups according
to BMI < 25 (lean group) & > 25 (obese group)
prostate! Matsuda T, Abe H, Suda K. Relation between benign prostatic hyperplasia and obesity
and estrogen] Rinsho Byori. 2004 Apr;52(4):291-4 Department of Pathology, Juntendo
University School of Medicine, Bunkyo-Ku, Tokyo

3
 Obesity => serum E2 Estradiol in obese
Men with benign prostate hyperplasia
younger than 60 yrs persons Obese men
= or > 140% over
Figure: Sign. elevated the serum
Underweight Obese > or = 140 % oestradiol level in obese men .

Serum
60
recommended weight Abundant hormone in men
60
recommended
weight
Average prostate specimen
weights increased with
50 increasingly obesity & increasing
52,3 Underweight
Estradiol 40 pg/ml Serum men younger 51.3 host age from 46 to 80 g.
30
(pg/mL) Estradiol 40 > 60 yrs
The degree of obesity has a direct
20 26.8 (pg/ml) effect on oestradiol levels through
10 pg/ml 26.8
20 transformation of androgens in
0
P < 0.01 adipose tissue to oestrogens.
Fig.: Average specimen weights increased with increasingly obesity & Despite the larger adenomas, no
increasing host age from 46 to 80 g. The serum oestradiol was sign. elevated in increase in the symptom score for
0
obese men who were 140% or over recommended weight vs underweight men BPH was observed with
younger than 60 yrs. n = 68 men + benign prostatic hyperplasia
n = 68 men with benign prostatic hyperplasia Oettel M, Mukhopadhyay AK. Progesterone: increasing
the forgottenobesity.
hormone in men?
Kpeli B, Soygr T, Aydos K, Ozdiler E, Kpeli S. The role of cigarette smoking in prostatic enlargement. Soygur T, Kupeli B, AydosAging
K, Kupeli
Male.S, Arik
2004an N, Muftuoglu YZ. Effect of obesity on prostatic
Sep;7(3):236-57
Br J Urol. 1997 Aug;80(2):201-4. SSK Diskapi Hospital, Ankara, Turkey. hyperplasia: its relation to sex steroid levels. Int Urol Nephrol.1996;28(1):55-9. Un. Ank ara, Turk ey

Smoking
=> E2

Smoking => serum E2 (& testo)

Men with benign prostate hypertrophy

Serum
Estradiol

(pg/mL)
40

30

20
Nonsmokers

26.7
pg/ml
Smokers

33.8
pg/ml
Age =>
the Prostate
10

0
P < 0.01
Fig.: Current cigarette smokers had sign. higher mean serum E2 than did the
non-smokers. Smoking was invers. but not sign. rel. to serum testost.
n = 68 men + BPH (mean age 59 years, range 52-74)
Kpeli B, Soygr T, Aydos K, Ozdiler E, Kpeli S. The role of cigarette smoking in prostatic enlargement.
Br J Urol. 1997 Aug;80(2):201-4. SSK Diskapi Hospital, Ankara, Turkey.

4
 serum free testo + rel. serum E2
with advancing age => BPH?
SUBJECTS: 61 patients subj. to prostatectomy for benign prostatic
hyperplasia (BPH); 45 controls without any lower urinary tract s. .

BPH =>
RESULTS:
sign. Prostate adenoma weight (p = 0.02) with advancing age in clinical
BPH group.
Sign. serum serum estradiol when adenoma weight of > 50 g (p = 0.047)
No diff. between serum of other sex horm. between small & large prostates
Sign. age-rel. serum free testosterone & serum estradiol, prolactin &
gonadotropin levels
Sign. serum free testosterone in controls (without prostate
hypertrophy) forages 60-69 (p = 0.015) serum total testosterone in
BPH patients for patients > 70 years of age (p = 0.027).

serum E2
Age-dep. serum in serum E/freeT ratio in both clinical BPH & control
patients whereas serum freeT/T ratio was decreased in the BPH group
with advancing age (p = 0.008).
CCL: The serum free testosterone + relative serum estradiol with
advancing age might = important factor in the development of BPH
Tan MO, Karabiyik I, Uygur MC, Diker Y, Erol D. Serum concentrations of sex
hormones in men with severe lower urinary tract symptoms and benign prostatic
hyperplasia. Int Urol Nephrol. 2003;35(3):357-63. Department of Urology, Faculty of
Medicine, Gazi University, Ankara, Turkey. mozgurtan@yahoo.com

An estrogen-dominant environment plays an Predominance of estrogens

important role in the development of BPH
SUBJECTS: Men who attended the mass screening for prostate disease over androgens in BPH
RESULTS:
No sign. correlations between total testo. levels, free testo levels, & SUBJECTS: patients with BPH (benign prostatic hypertrophy) &
prostate size (as determined by digital rectal examination) control men.
Serum E2 & the ratios for E2 levels such as the ratios for RESULTS: in the BPH group (vs control group)
E2/Total-T & E2/Free-T were sign. correlated with
prostate size.
significantly lower Serum testosterone
To confirm these relationships were confirmed when the prostate
volume was calculated from transrectal ultrasonographic images: Serum FSH, LH, prolactin & E2, did not differ sign.
Serum E2 levels & the 2 ratios were, indeed, highly correlated with
prostate volume. T
=> increased E2 / testo ratio
CCL: An estrogen-dominant environment plays an important
role in the development of BPH.
Suzuki K, Ito K, Ichinose Y, Kurokawa K, Suzuki T, Imai K, Yamanaka H, Honma S. Endocrine environment
of benign prostatic hyperplasia: prostate size and volume are correlated with serum estrogen concentration. Ortega E, Ruiz E, Mendoza MC, Martin-Andres A, Osorio C. Plasma steroid and
Scand J Urol Nephrol. 1995 Mar;29(1):65-8. Suzuki K, Inaba S, Takeuchi H, Takezawa Y, Fukabori Y, Suzuki T, Imai protein hormone concentrations in patients with benign prostatic hypertrophy and in
K, Yamanaka H, Honma S. [Endocrine environment of benign prostatic hyperplasia--relationships of sex steroid hormone
normal men. Experientia. 1979 Jun 15;35(6):844-5.
levels with age and the size of the prostate] Nippon Hinyokika Gakkai Zasshi. 1992 May;83(5):664-71

Predominance of estrogens Prostate hypertrophy => higher

over androgens in BPH & PC oestradiol & lower progesterone
SUBJECTS: 9 patients + untreated prostatic cancer & 11
with benign prostatic hypertrophy (BPH). The elderly subject
with an adenoma had
RESULTS: Basal levels & responses to hCG stimulation =>
no specific changes in steroid hormone levels in either
a serum
disease group were found => response patterns of serum progesterone level &
T, DHT, & E2 were shown to be those characteristic of oestrogen levels vs
male senescence, suggesting a relative predominance of the elderly subject
estrogens over androgens. Neither androsterone (A), 5-alpha- not suffering from a
androstane-3 alpha, 17 beta-diol (5 alpha-diol) A exhibited prostatic adenoma
appreciable responses to hCG stimulation in our study Baranowska B, Zgliczynski S, Szymanowski J. Hormonal disturbances in
Isurugi K, Kanazawa M, Yanaihara T, Kambegawa A. Responses of serum levels of
testicular steroid hormones to hCG stimulation in patients with prostatic cancer and men with a prostatic adenoma. J Urol (Paris). 1980;86(7):551-8
benign prostatic hypertrophy. Prostate Suppl. 1981;1:19-26

5
 Progesterone ESTROGEN PROSTATE
p < 0.0005
Can reduces prostate
stroma
120
100 90.5 96.0
74.0 79,8
80 72.2
(in % of 60
total
Estradiol levels, prostate
40
20
volume) 0
> 14estrogen
major trigger
2.5 - 5.0 5.1 - 8.0 8.1 - 11.0 11.1-14.0
excretion
(g/24 h)
Figure : there is a highly significant increase of prostate stroma
in men in association with higher individual estradiol

for BPH urinary excretion (and estradiol plasma

concentrations). (Seppelt U, J Clin Endoc Metab, 1978, 47: 1230)
T. Hertoghe, 11-1999, Brussels

Prostate stromal hyperplasia

High E2 in prostate hyperplasia only in presence of E2
SUBJECTS: Men
SUBJECTS: young (< 40 months) beagles with spontaneous
RESULTS: benign prostatic hyperplasia (BPH) were not sign. (P >
No sign. correlations between Total-T levels, Free-T 0.25)diff. from serum hormone levels of age matched
levels, & prostate size by digital rectal examination. controls, or old (> 60 months) beagles with BPH. However,
BPHis not associated with increased serum concentrations of
Digital rectal exam: E2 levels & the ratios
androgens, or changes in serum levels of gonadotropins, but
for E2/Total-T& E2/Free-T were may be related to some change in estrogen biosynthesis or
sign. assoc. with prostate size . metabolism.
Transrectal US of prostate volume prostate weight was increased by steroid treatments which
=> E2 levels & these 2 ratios were elevated the serum DHT. Glandular hyperplasia,
indistinguishable from that seen in dogs with BPH, occurred
highly correlated with prostate volume. only when E2 was added to those steroid treatments which
CCL: an estrogen-dominant environment plays an caused elevated serum DHT
important role in the development of BPH.
Suzuki K, Ito K, Ichinose Y, Kurokawa K, Suzuki T, Imai K, Yamanaka H, Honma S.
Cochran RC, Ewing LL, Niswender GD. Serum levels of follicle stimulating hormone,
Endocrine environment of benign prostatic hyperplasia: prostate size and volume are
luteinizing hormone, prolactin, testosterone, 5 alpha-dihydrotestosterone, 5 alpha-
correlated with serum estrogen concentration. Scand J Urol Nephrol. 1995 Mar;29(1):65-8.
androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, and 17
Department of Urology, School of Medicine, Gunma University, Japan.
beta-estradiol from male beagles with spontaneous or induced benign prostatic
hyperplasia. Invest Urol. 1981 Nov;19(3):142-7

Aromatse inhibitor => E => prostate size

recent studies in animal models and in men have shown that estrogens
Prostate hypertrophy => higher
might be causally linked to the onset and maintenance of BPH, we
examined the effect of1-methyl-androsta-1,4-diene-3,17-dione (Atamestane),
oestradiol & lower progesterone
a newly developed aromatase inhibitor, in men with BPH.
STUDY: open multicenter study 49 men (mean age 70.1years, range 55 to The elderly subject with an adenomahad
84) with obstructive BPH were treated with atamestane (3 x200 mg/day) for 3
months. Of the 49 patients 44 completed the treatment period; the other
a lower serum progesterone level. &
patients discontinued the study for reasons unrelated to treatment. higher oestrogen levels vs the elderly
RESULTS: With treatment BPH-related symptoms such as daytime voiding
frequency, nycturia, peak flow & residual urine improved considerably; subject not suffering from a prostatic
however, these parameters did not reach statistical significance. The mean
prostatic volume decreased significantly from 74.2 +/- 31.7 to 64.0 +/- 31
adenoma
ml (mean +/- SD). Serum estrogen levels decreased markedly during
treatment. In addition intraprostatic estrogen concentration decreased
with treatment as compared to estrogen levels in hyperplastic prostates
from untreated patients. CCL: 1) estrogens => impt supportive role in
established BPH, & 2) estrogen deprivation => BPH-related symptoms
& sign. prostatic volume.
Schweikert HU, Tunn UW, Habenicht UF, Arnold J, Senge T, Schulze H, Schroder FH,Blom
Baranowska B, Zgliczynski S, Szymanowski J. Hormonal disturbances in
JH, Ennemoser O, Horniger W, et al. Effects of estrogen deprivation on human benign
men with a prostatic adenoma. J Urol (Paris). 1980;86(7):551-8
prostatic hyperplasia. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):573-6. Department of
Internal Medicine, University of Bonn, Germany.

6
 High E2 & E3 in
prostate hyperplasia
SUBJECTS: 64 men ages 42 to 71 years with low volume
prostatic cancer => serum hormones levels were
correlated with the volume of benign hyperplastic tissue
in their radical prostatectomy specimens
RESULTS: When benign prostatic hyperplasia (BPH)
volume & hormone levels were corrected for age, BPH
volume correlated positively with free testosterone,
estradiol, & estriol.
CCL: Men with larger volumes of BPH have higher serum
Partin AW, Oesterling JE, Epstein JI, Horton R, Walsh PC. Influence of age and
androgen & estrogen levels
endocrine factors on the volume of benign prostatic hyperplasia. J Urol. 1991
Feb;145(2):405-9. James Buchanan Brady Urological Institute, Baltimore, Maryland.
High E2/low bioavail Testo =>
increased prostate volume
SUBJECTS: Men , 320; median age, 60.9 years, cross-sect.
RESULTS:
Bioavailable testo levels declined with increasing cross-
sectional age from 53.8,50.2, to 41.2 ng/dl (P = 0.001) in
men aged <60, 60-69, & >69 years, resp., &
the E2/bioavailable testo ratio increased from 0.042, 0.044, to
0.050 (P = 0.04).
Among men with bioavailable testo above the median, E2
levels had a dose response relationship with prostate size.
Among men with bioavailable testosterone level </= the
median, however, there was no association between E2
level & prostate volume
Roberts RO, Jacobson DJ, Rhodes T, Klee GG, Leiber MM, Jacobsen SJ. Serum sex
hormones and measures of benign prostatic hyperplasia. Prostate. 2004 Oct 1;61(2):124-31.
Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic College of
Medicine, Rochester, Minnesota, USA. roberts.rosebud@mayo.edu
High E2=> increased prostate
volume
SUBJECTS 312 men (mean age 62.8 +/-10.6 years, range 40
to 91) with lower urinarytract symptoms (LUTS) vs Men (40
years old or older) with untreated LUTS as defined by
anInternational Prostate Symptom Score (IPSS) of 7 or
greater due to benign prostatic hyperplasia
RESULTS:
E2 (but not testo) correlated (r = 0.17, P = 0.01) with
prostate volume. The peak flow rate & PSA did not
correlate with any endocrinologic parameter.
Hypogonadism (serum testo < 3.0 ng/mL) in 22.1% of
patients & had no impact on clinical (IPSS, peak flow rate,
prostate volume, and PSA level)
Schatzl G, Brossner C, Schmid S, Kugler W, Roehrich M, Treu T, Szalay A, Djavan B,
Schmidbauer CP, Soregi S, Madersbacher S. Endocrine status in elderly men with
lower urinary tract symptoms: correlation of age, hormonal status, and lower urinary
tract function. The Prostate StudyGroup of the Austrian Society of Urology. Urology.
2000 Mar;55(3):397-402. Department of Urology, University of Vienna, Vienna, Austria.
High E2 in prostate
SUBJECTS: Men hyperplasia
RESULTS:
No sign. correlations between Total-T levels, Free-T levels,
& prostate size by digital rectal examination.
E2 levels & the ratios for E2 levels and the ratios for
E2/Total-T and E2/Free-T were sign. correlated with
prostate size.
To confirm these relationships, prostate volume =>
transrectal ultrasonographic images. E2 levels & these
two ratios were highly correlated with prostate volume.
CCL: an estrogen-dominant environment plays an
important role in the development of BPH.
Suzuki K, Ito K, Ichinose Y, Kurokawa K, Suzuki T, Imai K, Yamanaka H, Honma S.
Endocrine environment of benign prostatic hyperplasia: prostate size and volume are
correlated with serum estrogen concentration. Scand J Urol Nephrol. 1995 Mar;29(1):65-8.
Department of Urology, School of Medicine, Gunma University, Japan.
High E2=> increased prostate
volume
SUBJECTS: Men , 320; median age, 60.9 years, cross-sect.
RESULTS:
No difference between serum sex hormones & small & large
prostates except for serum E2 => sign. higher in patients
who had an adenoma weight of > 50 g (p = 0.047).
Similar results in both clinical BPH & control groups with
respect to age-related changes in serum sex hormones.
an age-related decrease in serum free testosterone levels &
increase in serum E2, prolactin & gonadotropin levels.
An age-dep.t increase in serum E/freeT ratio in both clinical
BPH & control patients serum freeT/T ratio : decreased
in the BPH group with advancing age (p = 0.008).
Tan MO, Karabiyik I, Uygur MC, Diker Y, Erol D. Serum concentrations of sex hormones in
men with severe lower urinary tract symptoms and benign prostatic hyperplasia. Int Urol
Nephrol. 2003;35(3):357-63. Department of Urology, Faculty of Medicine, Gazi University,
Ankara, Turkey.mozgurtan@yahoo.com
High E2=> no effect on
prostate volume
SUBJECTS 52 patients with histologically
confirmed BPH and 52 healthy controls
RESULTS:
T and E2 were not significantly related to the risk of
BPH.
Lagiou P, Mantzoros CS, Tzonou A, Signorello LB, Lipworth L,
Trichopoulos D. Serum steroids in relation to benign prostatic hyperplasia.
Oncology. 1997 Nov-Dec;54(6):497-501. Department of Epidemiology,
Harvard School of Public Health, Boston, MA 02115,USA.
7
 High E2=> no effect on prostate volume 1 High E2=> no effect on prostate volume 2

SUBJECTS: pregnant mice SUBJECTS: pregnant mice

RESULTS: a 50% increase in free-serum estradiol in male
mouse fetuses (released by a maternal Silastic estradiol
implant) induced a 40% increase in the number of developing
prostatic glands during fetal life; subsequently, in adulthood,
the number of prostatic androgen receptors per cell was
permanentlyincreased by 2-fold, and the prostate was
enlarged by 30% (due to hyperplasia) relative to untreated
males. However, as the free serum estradiol concentrationin
male fetuses was increased from 2- to 8-fold, adult prostate
weight decreased relative to males exposed to the 50%
increase in estradiol.
vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar
MD,Ganjam VK, Parmigiani S, Welshons WV. Prostate enlargement in mice due
to fetal exposure to low doses of estradiol ordiethylstilbestrol and opposite effects
at high doses. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2056-61. Division of
Biological Sciences, University of Missouri-Columbia, 65211,
USA.vomsaal@biosci.mbp.missouri.edu
RESULTS: As a model for fetalexposure to man-made
estrogens, pregnant mice were fed diethylstilbestrol (DES)
from gestation days 11 to 17. Relative to controls, DES doses
of 0.02, 0.2, and2.0 ng per g of body weight per day increased
adult prostate weight, whereas a 200-ng-per-g dose
decreased adult prostate weight in male offspring.
CCL: a small increase in estrogen may modulate the action
ofandrogen in regulating prostate differentiation, resulting in
a permanent increase in prostatic androgen receptors and
prostate size. For both estradiol and DES, prostate weight
first increased then decreased with dose, resulting inan
inverted-U dose-response relationship.
vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar
MD,Ganjam VK, Parmigiani S, Welshons WV. Prostate enlargement in mice due
to fetal exposure to low doses of estradiol ordiethylstilbestrol and opposite effects
at high doses. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2056-61. Division of
Biological Sciences, University of Missouri-Columbia, 65211,
USA.vomsaal@biosci.mbp.missouri.edu

Lower testo in BPH

SUBJECTS: patients with benign prostatic

hypertrophy & in normal men.
RESULTS: The testosterone concentrations in
the BPH group were significantly lower than
E2 =>
thatof the control group

Ortega E, Ruiz E, Mendoza MC, Martin-Andres A, Osorio C. Plasma steroid and

the Prostate
protein hormone concentrations in patients with benignprostatic hypertrophy and in
normal men. Experientia. 1979 Jun 15;35(6):844-5.

Estradiol (but not testosterone) correlated

(r = 0.17, P = 0.01) with prostate volume ESTROGEN PROSTATE
p < 0.0005
SUBJECTS: 312 Men (40 years old or older; mean 120
age 62.8 +/-10.6 years, range 40 to 91) ) with Prostate 100 90.5 96.0
untreated LUTS as defined by an International stroma 74.0 79,8
80 72.2
Prostate Symptom Score (IPSS) of 7 or greater due
to benign prostatic hyperplasia (in % of 60
total
40
RESULTS: prostate
volume) 20
Estradiol (but not testosterone) correlated (r = 0
0.17, P = 0.01) with prostate volume 2.5 - 5.0 5.1 - 8.0 8.1 - 11.0 11.1-14.0 > 14 estrogen
Hypogonadism (serum testosterone < 3.0 excretion
(g/24 h)
ng/mL) was detected in 22.1% of patients Figure : there is a highly significant increase of prostate
stroma in men in association with higher individual
Schatzl G, Brssner C, Schmid S, Kugler W, Roehrich M, Treu T, Szalay A, Djavan B, Schmidbauer CP, estradiol urinary excretion (and estradiol plasma
Sregi S, Madersbacher S. Endocrine status in elderly men with lower urinary tract symptoms: correlation of concentrations). (Seppelt U, J Clin Endoc Metab, 1978, 47: 1230)
age, hormonal status, and lower urinary tract function. The Prostate Study Group of the Austrian Society of T. Hertoghe, 11-1999, Brussels
Urology. Urology. 2000 Mar;55(3):397-402. Department of Urology, University of Vienna, Vienna, Austria

8
 ESTROGENS & ANDROGENS PROSTATE

Human TOTAL PROSTATE

VOLUME
CENTRAL PROSTATE
anabolic
steroids
VOLUME
androgens* +20%

Studies: 20
10
prostate 0
volume-10
(anabolic
steroids)

-2%
Estrogens Estrogens

Estrogen -20
-30
-40
-50
-31%

-46%

treatment Figure : Different effects of androgenic anabolic steroids in

athletes and of estrogen therapy in male to female
transsexuals on their prostate.
(Jin B et al, J Clin Endoc Metab, 1996, 81: 4290-4295)
T. Hertoghe, 11-1999, Brussels

E2 to PC patients => hgher TBG,

lower free T4
Patients with prostate cancer => treated with
Human
estrogens after orchiectomy.
RESULTS: Low-dose estrogen treatment for
> 6 months => stimulates the synthesis of
Studies:
thyroxine-binding globulin. => serum level
of thyroxine is also increased, but serum
free thyroxine is distinctly lowered by
Estrogen
estrogen treatment => the linear ratio of
thyroxine and free thyroxine is disturbed.
Dunzendorfer U, Schulz H..Thyroid hormones in metastasizing prostate
cancer treated with polyestradiolphosphate Z Urol Nephrol. 1982
depletion
Jul;75(7):493-500

EStrogen depletion reduces prostate size EStrogen depletion reduces prostate size
SUBJECTS: healthy 154 men, ages from 18 to 91 years old.
Schweikert HU, Tunn UW, Habenicht UF, Arnold J, Senge T, Schulze H, Schroder In 59 men, prostatic size was estimated by digital
FH,Blom JH, Ennemoser O, Horniger W, et al. Effects of estrogen deprivation on human examination & 3 groups: < or= to walnut size, small hen's
benign prostatic hyperplasia. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):573-6.
Department of Internal Medicine, University of Bonn, Germany. egg size & = to or larger than hen's egg size.
Sex steroids are thought to play an essential role in the pathogenesis of humanbenign RESULTS:
prostatic hyperplasia (BPH). Since recent studies in animal models and inmen have
shown that estrogens might be causally linked to the onset andmaintenance of BPH, we a slight decrease in Total-T over 60years old, a significant
examined the effect of1-methyl-androsta-1,4-diene-3,17-dione (Atamestane), a newly decrease in Free-T, and no change in E2 with age. E2/Total-
developed aromataseinhibitor, in men with BPH. In an open multicenter study 49 men
(mean age 70.1years, range 55 to 84) with obstructive BPH were treated with T & E2/Free-T ratio increased sign. after middle-age.
atamestane (3 x200 mg/day) for 3 months. Of the 49 patients 44 completed the Inthe larger prostate group, a sign. lower Total-T & sign.
treatment period;the other patients discontinued the study for reasons unrelated to
treatment.With treatment BPH-related symptoms such as daytime voiding frequency, higher E2. But there was no difference in Free-T.
nycturia,peak flow and residual urine improved considerably; however, these
parametersdid not reach statistical significance. The mean prostatic volume the prostatic size was correlated positively with E2
decreasedsignificantly from 74.2 +/- 31.7 to 64.0 +/- 31 ml (mean +/- SD). Serum level,E2/Total-T & E2/Free-T ratio.
estrogenlevels decreased markedly during treatment. In addition intraprostatic
estrogenconcentration decreased with treatment as compared to estrogen levels CCL: the endocrine environment tended to be estrogens-
inhyperplastic prostates from untreated patients. The following conclusions can bedrawn dominant with age, in particular, after middle-age, & that
from this study: first, estrogens appear to have an important supportiverole in patients with large prostates have more estrogens-
established BPH, and second, estrogen deprivation improved BPH-relatedsymptoms Suzuki K, Inaba S, Takeuchi H, Takezawa Y, Fukabori Y, Suzuki T, Imai K, Yamanaka H, Honma
and reduced significantly prostatic volume. dominant
S. environments.
[Endocrine environment Estrogens
of benign prostatic are key hormones
hyperplasia--relationships for
of sex steroid hormone
the levels
induction and
with age and the the
size ofdevelopment
the prostate] Nippon of BPH.Gakkai Zasshi. 1992
Hinyokika
May;83(5):664-71. Division of Urology, Shakai Hoken Mishima Hospital.

9
 EStrogen depletion reduces prostate size

E2 =>
SUBJECTS: young (< 40 months) beagles with spontaneous
benignprostatic hyperplasia (BPH) were not significantly (P >
0.25)different from serum hormone levels of age matched
controls, or old (greaterthan 60 months) beagles with BPH.
However, the serum hormone levels of agematched controls,
or with BPH (2.46 +/- 0.51 pg per ml) was sign. (P < 0.05) lower
than that of age matched controls (3.93 +/- 0.35 pg per ml) &
of old beagles with BPH is not associated with increased
serum concentrations of androgens, or changes in serum
levels of gonadotropins, but may be related to some change
in estrogen biosynthesis or metabolism.
prostate weight was increased by steroid treatments which
elevated the serum DHT. Glandular hyperplasia,
the Prostate
indistinguishablefrom that seen in dogs with BPH, occurred
only when E2 was added to those steroid treatments which
caused elevated serum DHT
Cochran RC, Ewing LL, Niswender GD. Serum levels of follicle stimulating hormone,
luteinizing hormone, prolactin, testosterone, 5 alpha-dihydrotestosterone, 5 alpha-
androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, and 17
beta-estradiol from male beagles with spontaneous or induced benign prostatic
rodent studies
hyperplasia. Invest Urol. 1981 Nov;19(3):142-7

E2 => squamous metaplasia of

prostate glandular cells

Dog SUBJECTS: glands ofcastrated dogs

RESULTS: Treatment with 1 mg. of estradiol-
17 beta 17-cyclopentylpropionate (ECP)

Studies per week for 2 weeks => basal cell mitosis

and early squamous metaplasia.
The glandular epithelium hypertrophied but
was not repopulated.

Merk FB, Ofner P, Kwan PW, Leav I, Vena RL. Ultrastructural and biochemical
expressions of divergent differentiation in prostates of castrated dogs treated with
estrogen and androgen. Lab Invest. 1982 Nov;47(5):437-50.

E2 & DHT => BPH in dogs

Prostate glandular hyperplasia,

Rat
indistinguishable from that seen in dogs
with BPH, occurred only when estradiol was
added to those steroid treatments which
Studies
caused elevated serum DHT

Cochran RC, Ewing LL, Niswender GD. Serum levels of follicle stimulating hormone,
luteinizing hormone, prolactin, testosterone, 5 alpha-dihydrotestosterone, 5 alpha-androstane-
3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, and 17 beta-estradiol from
male beagles with spontaneous or induced benign prostatic hyperplasia. Invest Urol. 1981
Nov;19(3):142-7

10
 Accumulation of collagen, non-collagenous
protein & elastin in prostates of E2-treated
Perinatal or neonatal exposure of rats rats => suppressed degradation of biosynthesis of these
connective tissue proteins.
& mice to estrogens
Oestradiol-17 beta-treated rats vs vehicle-treated rats:
=> "imprinting" of prostate associated concentrations of collagen, non-collagenous protein & elastin
in ventral & dorsolateral prostates in
with increased proliferation, in vivo incorporation rates of 3H-proline into these connective
inflammation & dysplastic epithelial tissue proteins in ventral & dorsolateral prostates
changes later in life. lowest degradation rate of 3H-proline incorporated into each
connective tissue protein
Ccl: the accumulation of collagen, non-collagenous protein &
elastin in prostates of E2 -treated rats <= largely caused by:
degradation of synthesis of connective tissue proteins.
Harkonen PL, Makela SI. Role of estrogens in development of prostate cancer. J Steroid Biochem Mol Biol. Nakada T, Kubota Y, Sasagawa I, Suzuki H, Watanabe M, Suzuki Y. The effect of
2004 Nov;92(4):297-305. Epub 2004 Dec 19. oestradiol-17 beta on connective tissue protein in rat prostate. Int Urol Nephrol.
1994;26(3):327-35. Department of Urology, Yamagata University School of Medicine,
Japan.

ESTROGENS, TESTOSTERONE & P4

PROSTATE (mice)

Mice ESTROGENS BUT

Progynon B,
Estrim
the weight + size of the PROSTATE & the SEMINAL
VESICLES* to approximately the same size as these present in
castrated mice
BUT :

Studies 1. THE EPITHELIUM UNDERGOES METAPLASIA : arrest of

function hyperplasia metaplasia stratified squamous
epithelium REVERSED BY TESTOSTERONE,
PREVENTED BY PROGESTERONE IF TESTOSTERONE**
2. THE FIBROMUSCULAR STROMA NO EFFECT OF TESTO
3. THE URINARY BLADDER DILATES DELAYED BY TESTO
4. SCROTAL HERNIAS APPEAR DELAYED BY TESTO
* : A large part of the volume is the result of the glands being distended
with secretion; in mice the fibromuscular stroma is a small % of the
rest; in dogs where the fibromuscular stroma is more important,
Progynon B the size + weight of prostate.
** : Burrows H, Nature (London), 1936, 138: 164

E2 => Prostate (mice): discrete lobe-specific changes,

incl. smooth-muscle regression, fibroblast proliferation, inflam- Estrogen & testosterone
mation, & basal epithelial cell proliferation & metaplasia => oxidative damage to prostate
INFO: Exogenous estrogen => inhibits prostate growth by indirect effects
caused by pituitary LH & FSH & testicular testosterone output,
SUBJECTS: Mature hypogonadal mice + sc implants + E2.
RESULTS: After 6 wk, E2:
Sign. prostate volumes [anterior prostate (AP) & ventral prostate (VP)]
estrogen, in the presence of testosterone, causes
& seminal vesicle lobe organ volume (SV) (P < 0.05) but remained
smaller than wild-type mice.
Sign. in cellular & luminal volumes (P < 0.05) in anterior prostate (but
not ventral prostate) & in seminal vesicles prolonged activation of a redox-sensitive
Stromal fibroblast proliferation smooth muscle cells in AP & SVs.
In the epithelia, basal cells proliferated & became metaplastic in the AP transcription factor, nuclear factor kappa B
& VP.
=> Initiates & inflammatory cascade within the
In the anterior prostate (AP), luminal debris accumulated, together with
an inflammatory response, but there was no evidence of malignant
changes.
CCL: direct proliferative responses to E2 in the hypogonadal mouse AP & prostate => sustained oxidative damage.
VPlobes & SVs, characterized by discrete lobe-specific changes, incl.
smooth-muscle regression, fibroblast proliferation, inflammation, &
basal epithelial cell proliferation & metaplasia.
Bianco JJ, Handelsman DJ, Pedersen JS, Risbridger GP. Direct response of the murine prostate gland and
seminal vesicles to estradiol. Endocrinology. 2002;143(12):4922-33.
Centre for Urological Research, Monash University, Clayton, Victoria, 3168,Australia.

11

Monkey
Studies
Androgens => reduce estrogen
receptors in the prostate
We examined nuclear estrogen receptors (ER) and progestin receptors (PR) in therhesus monkey
prostate. Tissues were obtained from six intact males, fiveuntreated castrates, six castrates treated with
testosterone (T) for 6 weeks,and four castrates treated with estradiol (E2) for 6 weeks. Samples of
thecaudal lobe were either assayed biochemically for ER or stainedimmunocytochemically (ICC) with
monoclonal antibodies against the ER or PR.Prostates from untreated castrates had significantly more
ER than tissues fromintact or T-treated castrates. In E2-treated castrates, ER number
increasedcompared to that in intact and T-treated castrates. With ICC, ER was found onlyin the nuclei of
the fibroblasts and smooth muscle cells of the stroma, not theglandular, ductal, or urethral epithelial cells.
Intact and T-treated castrateshad a very small number of positive cells, while untreated and E2-
treatedcastrates had a significantly increased number of positive ER cells in thefibromuscular stroma.
With ICC, PR was absent in intact or T-treated animals andbarely evident in untreated castrates, but was
significantly increased in thefibromuscular stroma of E2-treated castrates. The histological
preparationsindicated there was no stromal hypertrophy in the E2-treated castrates, but theE2 treatment
did cause dilation of the glandular acini. Aromatase activity wasmeasured in prostatic microsomes with a
radiometric assay. Levels were low (3-30fmol/h.mg protein) compared to those in brain and placenta,
and no differencesin activity were seen between castrates and T-treated castrates.
CCL Our data demonstrate that androgens can suppress the level of
nuclear ER in the rhesus prostate, and that E2 treatment of castrates can
induce PR in the same cells asthose that contain ER. Thus, under appropriate conditions, estrogens
couldaffect the rhesus prostate through a receptor-mediated pathway.PMID: 3262505 [PubMed - indexed
for MEDLINE]
Endocrinology. 1988 Nov;123(5):2312-22. Estrogen and progestin receptors and aromatase activity in rhesus
monkeyprostate.West NB, Roselli CE, Resko JA, Greene GL, Brenner RM. Division of Reproductive Biology
and Behavior, Oregon Regional Primate ResearchCenter, Beaverton 97006.
In the absence of androgen the only direct effect of
estrogens on the prostate glandular cells = the
induction of squamous metaplasia in men
SUBJECTS: 4 men + benign prostatic hypertrophy who underwent
medical castration therapy + long-acting gonadotropin-releasing
hormone agonist(leuprolide) for > 6 months elected to add an
estrogen transdermal patch (0.05 mg. to the skin biweekly) to the
leuprolide regimen.
RESULTS:
The average prostatic size (transrectal ultrasound), serum prostate specific
antigen (PSA) levels andsymptoms of prostatism were dramatically decreased
with leuprolide alone.
Theaddition of estrogen for 6 months did not result in any change in prostate
size, symptoms or serum PSA levels over that seen with leuprolide alone.
In the absence of androgen the only direct effect of estrogens on the
prostate glandular cells = the induction of squamous metaplasia.
Levine AC, Kirschenbaum A, Droller M, Gabrilove JL. Effect of the addition of estrogen to medical castration
on prostatic size, symptoms, histology and serum prostate specific antigen in 4 men with benign prostatic
hypertrophy. J Urol. 1991 Sep;146(3):790-3. Bronfman Department of Medicine, Mount Sinai Medical
Center, New York, New York.
Estrogens => increase estrogen
receptors in the monkey prostate &
causes dilatation of glandular acini
We examined nuclear estrogen receptors (ER) and progestin receptors (PR) in the rhesus monkey prostate.
Tissues were obtained from six intact males, fiveuntreated castrates, six castrates treated with testosterone
(T) for 6 weeks,and four castrates treated with estradiol (E2) for 6 weeks. Samples of thecaudal lobe were
either assayed biochemically for ER or stainedimmunocytochemically (ICC) with monoclonal antibodies
against the ER or PR.Prostates from untreated castrates had significantly more ER than tissues fromintact or
T-treated castrates. In E2-treated castrates, ER number increased compared to that in intact and T-treated
castrates. With ICC, ER was found onlyin the nuclei of the fibroblasts and smooth muscle cells of the stroma,
not theglandular, ductal, or urethral epithelial cells. Intact and T-treated castrateshad a very small number of
positive cells, while untreated and E2-treatedcastrates had a significantly increased number of
positive ER cells in thefibromuscular stroma. With ICC, PR was absent in intact or T-
treated animals andbarely evident in untreated castrates, but was significantly increased in thefibromuscular
stroma of E2-treated castrates. The histological preparations indicated there was no stromal hypertrophy in
the E2-treated castrates, but the E2 treatment did cause dilation of the glandular
acini. Aromatase activity wasmeasured in prostatic microsomes with a radiometric assay. Levels were low
(3-30fmol/h.mg protein) compared to those in brain and placenta, and no differencesin activity were seen
between castrates and T-treated castrates.
CCL Our data demonstrate that androgens can suppress the level of nuclear ER in the
rhesus prostate, and that E2 treatment of castrates can induce PR in the same cells asthose that
contain ER. Thus, under appropriate conditions, estrogens couldaffect the rhesus prostate through a receptor-
Endocrinology. 1988 Nov;123(5):2312-22. Estrogen
mediated pathway.PMID: and progestin
3262505 [PubMed -receptors andMEDLINE]
indexed for aromatase activity in rhesus
monkeyprostate.West NB, Roselli CE, Resko JA, Greene GL, Brenner RM. Division of Reproductive Biology
and Behavior, Oregon Regional Primate ResearchCenter, Beaverton 97006.
E2 + DHT
=>
the Prostate
Men + larger volumes of BPH =>
serum androgen & estrogen levels
SUBJECTS: 64 men ages 42 to 71 years + low volume prostatic cancer
& these levels were correlated with the volume of benign
hyperplastic tissue in their radical prostatectomy specimens.
RESULTS:
With age => sign. in the volume of BPH.
with age => sign. in serum free testosterone, androstenedione,
DHEA , DHEA sulphate, delta 5-androstenediol, & 17-OH-
pregnenolone,
sign. SHBG, LH, & FSH.
When BPH volume & hormone levels were corrected for age, BPH
volume correlated positively with free testosterone, estradiol, &
estriol => with age patients with larger volumes of BPH have higher
serum androgen & estrogen levels => serum androgen & estrogen
levels may be => factors in the persistent stimulation of BPH with
age.
Partin AW, Oesterling JE, Epstein JI, Horton R, Walsh PC. Influence of age and endocrine
factors on the volume of benign prostatic hyperplasia. J Urol. 1991 Feb;145(2):405-9. James
Buchanan Brady Urological Institute, Baltimore, Maryland
12
 Combinat. of E2 + DHT => BPH in dogs
SUBJECTS: mongrel dogs treated for 60 days + implant + E2 + DHT =>
(1) marked of stromal elements, esp. the stromal septa between glands
(2) aslight in prostatic volume
(3) morphology = spontaneous benign prostatic hyperplasia
Other animals - untreated or + only E2 or only DHT - did not develop BPH
Prostate volumes by -14% in estrogen-treated dogs, whereas they
in the DHT-treated animals by 6% vs pretreatment prostate volumes.
Treatment
The morphology of prostate epithelium of DHT-treated animals was not
diff. from that of controls despite the in prostate volume.
The serum 17 E2 & DHT levels from 25 & 256 pg/mL, resp., in control
dogs to 52 & 562 pg/mL, resp., in dogs treated + hormone combin. =>
2- to 3 -fold than control values, & ratio of E2 to DHT by up to 19%.
CCL: treatment of dogs with low levels of estrogen + androgen => benign
prostatic hyperplasia such as in aging men.
Winter ML, Bosland MC, Wade DR, Falvo RE, Nagamani M, Liehr JG. Induction of benign prostatic
hyperplasia in intact dogs by near-physiological levels of 5 alpha-dihydrotestosterone and 17 beta-estradiol.
Prostate. 1995 Jun;26(6):325-33. Department of Pharmacology and Toxicology, University of Texas
Medical Branch, Galveston 77555-1031, USA

Increase in prostate hypertrophy Increase in prostate hypertrophy

(w/ eventually increased dysuria) (with eventually increased dysuria)
Treatment :
Cause:
1. Generally, occurs when testosterone administration 1. Treat the cause that favours the conversion
(through its conversion into estradiol by the aromatase) of androgens into estrogens: reduce or stop
increases substantially the estrogen levels. Prostate alcohol and caffeine consumption, reduce
hypertrophy is generally promoted by excessive levels fat mass by weight reduction diet, etc.
of estradiol as estrogens promote stromal hyperplasia 2. Stop the administration or the dose of
of the prostate. If this is the case, prostatism is more aromatisable (convertible into estrogens)
apparent and severe as the hypertrophy is easier androgens as testosterone, DHEA &
concentrated in the median area compressing the androstenedione
urether and presenting an obstacle to the urine flow is. 3. Replace partially or totally by natural (as
2. Such condition of prostate hypertrophy and high DHT) or synthetic derivatives non
estrogens levels occurs with testosterone, DHEA aromatisable androgens (as mesterolon,
and/or androstenedione administration, easier with stanozolol, )
regular alcohol or caffeine administration, obesity, etc.

MPA => reduces prostate hypertrophy Daidzin => serum testo, E2

(1) SUBJECTS: 80 patients + benign prostatic hyperplasia (BPH) in a double-blind,
placebo-controlled study. => depot medroxyprogesterone (DMPA), a 5 alpha-reductase,
luteinizing-hormone release & human androgen receptor adhesion inhibitor, or placebo
TREATMENT: one single 150 mg IM inj. of DMPA after 3 months (duration of DMPA
effect):
serum testosterone reached castration levels within 3 days as compared to no
changes in the placebo group;
the prostate volume was reduced by 25% vs a 3% decrease with placebo (p < 0.001);
maximum urinary-flow rates increased by 3.7 ml/s vs placebo (p < 0.001);
total urinary symptom scores decreased by 4.9 points vs a nonsign. decrease with
placebo (p < 0.005).
2.5-point decrease in irritative symptoms(urinary frequency, nocturia & urgency) vs a
nonsign. decrease with placebo (p < 0.005).
After 3 months
the urinary symptoms & urodynamic changes were reversed but sign. greater than the
baseline values (p < 0.001).
The prostates showed regrowth to the initial sizes within18-36 weeks.
DMPA was better tolerated, except for a higher incidence of impotence, decreased libido
and ejaculatory disorders, than in the placebo group.
The quality of life is improved with DMPA since it did not produce hotflashes.
CCL: single-dose DMPA 150 mg is a safe & effective treatment for prostatic obstruction
where potency is a secondary consideration .
Onu PE. Depot medroxyprogesterone in the management of benign prostatic hyperplasia. Eur
Urol. 1995;28(3):229-35 Department of Urology, Makurdi General Hospital, Nigeria.
prostate content & prostate hyerplasia
SUBJECTS: 40 healthy mice => 5 groups:
1.a normal controls ,
2.mice benign prostatic hyperplasia (BPH) treated by subcut. injection of
testosterone propionate
3.positive control group + BPH procedure treated by Qianliekang,
4. a 20 mg/(kg x d) 3'-daidzein sulfonate sodium (DSS) group + BPH procedure
&
5.a 40 mg/(kgx d) DSS group + BPH procedure.
RESULTS: after 12 days of DSS treatment (vs BPH model group):
dose-dep. prostate wet weight (P < 0.05) & index of prostate gland (P < 0.01)
The hyperplastic epithelioglandular papilla waned & even disappeared in the
DSS-treated groups under microscope => epithelial cells => cubical or flat.
Effect of DSS at 40 mg/(kg x d) = that of the positive anti-BPH drug
Qianliekang.
serum testosterone, estradiol contents & the T/E2 ratio (P < 0.05 or P < 0.01).
CCL: DSS => sign.antagonistic effect on BPH induced by testosterone prop. in
mice, which may involve its regulatory action on the sex hormone balance.
Huang YS, Zeng J, Huang YP, Qiu F, Ye HY, Wang SR. Antagonistic effect of 3'-daidzein
sulfonate sodium on prostatic hyperplasia in mice. Zhonghua Nan Ke Xue. 2007
May;13(5):387-90. Department of Pathophysiology, Huaxi School of Preclinical Sciences &
Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, China

13
 PROSTATE HYPERTROPHY :
TREATMENT
mechanism : urether compressed by prostate tissue,
mainly stromal (< E2) hyperslasia
treatment : - DHT or synthetic derivative of T
(not convertible to E2)
- URGENIN
- Zink
- Vit E
- PUFA
50 mg/day
400 800 mg/day
E2 &
- Mg2+ 300 600 mg/day
- oral/suppo PROGESTERONE 100 150 mg/day

- suppo Mg2+
- (saw palmetto 1/day)
7-30 days/month
Prostate Cancer?
- (finasteride : ProscarR 1/day)

120-fold greater incidence of clinically detected prostate

Prostate cancer
Prostate cancer = 2nd leading cause of cancer death
The incidence & mortality of prostate cancer = considerably lower in
Asian populations than in U. S. & European populations (Adlercreutz, H.
(1995) Phytoestrogens: epidemiology and a possible role in cancer protection. Environ.
Health Persp. 103:103-11243)
The incidence of precancerous lesions i= the same for these
populations (Chung, L. W. (1993) Implications of stromal-epithelial interaction in human
prostate cancer growth, progression and differentiation. Semin. Cancer Biol. 4:183-192)
Upon emigration to the United States, Asian men have a greater risk
for developing prostate cancer, & the earlier in life their arrival, the
more closely their risk approaches that of American men (Shimizu, H.,
Ross, R. K., Bernstein, L., Yatani, R., Henderson, B. E. & Mack, T. M. (1991) Cancers of the prostate and
breast among Japanese and white immigrants in Los Angeles County. Br. J. Cancer 63:963-966)
One of the major differences between Asian & Western populations is
diet. Asians have traditionally consumed a soy-based diet containing
isoflavones => higher genistein concentrations in the blood & urine
than those of American men (Adlercreutz, H., Markkanen, H. & Watanabe, S. (1993)
Plasma concentrations of phytoestrogens in Japanese men. Lancet 342:1209-1210; Denis, L., Morton, M.
S. & Griffiths, K. (1999) Diet and its preventive role in prostatic disease. Eur. Urol. 35:377-387)
cancer in the USA than in China little variation
worldwide of the incidence of latent prostate cancer => pr.
30% of men > 50 yrs + microfocal disease (autopsy studies)
J Natl Cancer Inst. 1995 Oct 4;87(19):1456-62. Comment in: J Natl Cancer Inst. 1995 Oct
4;87(19):1427-8. J Natl Cancer Inst. 1996 Jan 3;88(1):56-7.Decreased growth of established human
prostate LNCaP tumors in nude mice fed alow-fat diet.Wang Y, Corr JG, Thaler HT, Tao Y, Fair WR,
Heston WD.Department of Surgery, Sloan-Kettering Institute for Cancer Research, New York,NY 10021,
USA.BACKGROUND: Geographic variation in the incidence of clinically detected prostate cancer is
considerable, with a 120-fold greater incidence in the UnitedStates than in China. The incidence of latent
prostate cancer, however, showslittle variation worldwide, with approximately 30% of men older than age
50years having microfocal disease (determined by autopsy). Some epidemiologicstudies have suggested
that a high intake of dietary fat may constitute a riskfactor for the development of advanced prostate
cancer. PURPOSE: We studied theinfluence of dietary fat content on the growth of tumors established in
athymicnude mice with androgen-sensitive, human prostatic adenocarcinoma cells (LNCaPcells). We also
investigated whether manipulation of dietary fat content alteredprostate-specific antigen (PSA) production
by these tumors. METHODS: Tumors wereinduced in nude mice by subcutaneous injection of 10(6)
LNCaP cells. Both theAmerican Type Culture Collection (ATCC) LNCaP cell line and a moreandrogen-
responsive subline derived from it (i.e., the Harris LNCaP cell line)were used. Mice were fed a 40.5-kcal%
fat diet at the time of tumor cellinjection. Three weeks later, after measurable tumors were formed, the
animalswere assigned to receive diets with one of the following fat contents: 40.5,30.8, 21.2, 11.6, or 2.3
kcal% fat. Food intake, animal weights, and tumorvolumes were recorded weekly; serum PSA and
testosterone levels were measured atthe termination of the study. Post hoc multiple comparisons were
made using theStudent-Newman-Keuls procedure. Two-sided tests of statistical significance wereused to
evaluate pairwise comparisons. RESULTS: Tumor growth rates, final tumorweights, and ratios of final
tumor weights to animal weights were substantiallygreater in groups that continued to receive a 40.5-
kcal% fat diet than in groupswhose diets were changed to 2.3 kcal%, 11.6 kcal%, or 21.2 kcal% fat (all
Pvalues < .04). Comparison of these parameters among the 2.3-kcal%, 11.6-kcal%,and 21.2-kcal%
dietary fat groups did not reveal any statistically significantdifferences. No statistically significant
differences were noted in totalingested calories, animal weight gain, serum testosterone levels,
orhistopathologic characteristics of the tumors among the tested dietary groups.Serum PSA levels were
highest in the 40.5-kcal% fat group and lowest in the2.3-kcal% fat group (evaluated only for ATCC LNCaP
cells; P < .05). CONCLUSIONS:Reduction of dietary fat substantially slows the growth of tumors
establishedfrom human prostatic adenocarcinoma cells in a murine xenograft model Apositive

Prostate cancer
Low serum testo in men + PC
Factors associated w/ risk :
J Surg Oncol. 1990 Jun;44(2):122-8. Androgen, estrogen, and progesterone
receptor contents and serum hormone profiles in patients with benign
intake of calories, hypertrophy and carcinoma of the prostate. Kumar VL, Wadhwa SN, Kumar
V, Farooq A. Department of Pharmacology, All India Institute of Medical
Body Mass Index, Sciences, New Delhi. Cytosolic and nuclear androgen, estrogen and
progesterone receptor content was measured in the groups of 11 prostatic
consumption of animal fat carcinoma (PCA) and 32 benign prostatic hypertrophy (BPH) samples. All
BPH cases were positive for the cytosolic progesterone (PRc) and estrogen
receptor (ERc), whereas only 85% of cases (23/27) contained the androgen
receptor (ARc). Only those five patients who received estrogen treatment in
the PCA group had detectable ARc. PRc was present in all of the PCA
Factors associated w/ risk : cases, whereas ERc could be detected in only 82% (9/11) of cases.
Cytosolic contents of all three steroid receptors, however, were higher in the
Soy & other phytoestrogens intake PCA group. The level of nuclear steroid receptors, although present in fewer
cases in both groups, was higher than the cytoplasmic receptors. The
Selenium intake serum profile of estradiol, cortisol, and prolactin was normal in both groups,
whereas LH, FSH, and progesterone levels were higher than in normal
Vitamin A intake
(Xiao Z, Xu Q, Yuan Y. adults. Serum testosterone level was within normal range in the BPH group,
Solving the mystery of the but it was significantly below normal (P less than 0.005) in PCA patients.
PMID: 1693995 [PubMed - indexed for MEDLINE]
Serum vitamin D status & longevity of
centenarians in Bama. Chin J
Popul Sci. 1996;8(4):385-94)

14
 Prostate cancer => serum E2
Men
Prostate

E2 =>
Hypertrophy
40 Prostate
cancer
Serum 1 - 30 %
30
Estradiol
20 32.6 pg/ml; 25.8 pg/ml;
(pg/mL) +/- 12.6 +/- 12.7
10

Prostate Cancer?
P=P = 0.0003
Figure: The difference for serum estradiol between PC patients
& controls held true in all life-decades. Serum c DHEA-S &
testosterone were comparable between PC & control patients
n = 75 Patients + newly diagnosed, untreated prostate cancer (PC; & 159 controls po+ untreated lower
urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH)
Schatzl G, Reiter WJ, Thrridl T, Waldmller J, Roden M, Sregi S, Madersbacher S. Endocrine patterns
in patients with benign and malignant prostatic diseases. Prostate. 2000 Aug 1;44(3):219-24. Department
of Urology, University of Vienna, Vienna, Austria

Prostate cancer => serum E1 (+

testo & DHT in patients < 65 yrs)
Higher T less Prostate CA Men

Higher E more Prostate CA 100 Normal men

Prostate cancer
Patients

Serum 80 +72 %
Estrone 81 pg/ml
60
32.6 pg/ml;
40
(pg/mL) +/- 12.6
Stattin P et al. High levels of circulating testosterone 20
are not associated with increased prostate cancer 0
p < 0.001

risk: a pooled prospective study. Figure:Prostate cancer patients at all ages => high estrone, while
Int J Cancer. 2004 Jan 20;108(3):418-24. Prostate cancer atients younger than 65 yrs shwoed subnormal testosterone
averaged 282 ng/dl ( vs 434 ng/dl in controls (P < 0.0001) & DHT averaged 70
ng/dl in patients vs 99 ng/dl in controls (P< 0.01).
n =patients (aged 55-80) with stage C or D prostate cancer and36 normal men
Zumoff B, Levin J, Strain GW, Rosenfeld RS, O'Connor J, Freed SZ, Kream J, Whitmore WS, Fukushima
DK, Hellman L. Abnormal levels of plasma hormones in men with prostate cancer: evidence toward a "two-
disease" theory. Prostate. 1982;3(6):579-88

Low testo in prostate cancer Progesterone receptors in

Low androgen receptors in PC, but male primate reproductive organs
almost all patients have estrogen receptors Progesterone receptors in men
(mean +/- SE ) Pituitary Fig.: Male
SUBJECTS: 11 prostatic carcinoma (PCA) & 32 benign prostatic 1,5 gland monkey
hypertrophy (BPH) samples. reproductive
RESULTS: 1.3 tract
All BPH cases => positive for the cytosolic estrogen receptor (ERc), 1
contains mRNA
whereas only 85% of cases (23/27)contained the androgen receptor Epididymis for progesterone
(ARc). Testis (caput) recptors (PR)
Prostate with regional
Only those 5/11 patients + estrogen treatment in the PCA group had Epididymis
0,5
detectable ARc. 0.5 variation in their
(mean)
0.4 0.2 0.1 expression
The serum profile of estradiol, cortisol, & prolactin was normal in
both groups, whereas LH &FSH were higher than in normal adults.
Serum testosterone level was within normal range in the BPH group, 0

but it was sign. below normal (P < 0.005) in PCA patients. n = adult male cynomolgous monkeys

Kumar VL, Wadhwa SN, Kumar V, Farooq A. Androgen, estrogen, and progesterone receptor contents and Heik inheimo O, .,Gibbons WE. Estrogen and progesterone receptor mRNA are expressed in distinct
serum hormone profiles in patients with benign hypertrophy and carcinoma of the prostate. J Surg Oncol. pattern in male primate reproductive organs. J Assist Reprod Genet. 1995 Mar;12(3):198-204
1990 Jun;44(2):122-8. Department of Pharmacology, All India Institute of Medical Sciences, New Delhi

15
 E2 & Prostate Cancer : An anti-estrogen blocks prostate
The Experiments cancer growth in mice while
increasing testo levels
Mice without ER alpha or aromatasecan Raghow S, Hooshdaran MZ, Katiyar S, Steiner MS. Toremifene prevents prostate cancer in the transgenic
adenocarcinoma of mouse prostate model. Cancer Res. 2002 Mar 1;62(5):1370-6University of Tennessee
never get prostate cancer Urologic Research Laboratories, Memphis, Tennessee38163, USA. sraghow@utmem.edu The chemopreventive
efficacy of toremifene, an antiestrogen, was evaluated inthe transgenic adenocarcinoma of mouse prostate
(TRAMP) model. TRAMP mice weresegregated into three groups: (a) the low-dose toremifene group (6.6
Risbridger GP, Bianco JJ, Ellem SJ, McPherson SJ. Oestrogens and prostate cancer. Endocr Relat Cancer. mg/kg/day);(b) the high-dose toremifene group (33 mg/kg/day); and (c) the control placebogroup. Efficacy of
2003;10:187191. doi: 10.1677/erc.0.0100187 treatment was measured by the absence of palpable tumor. Toextend these studies using more sensitive
techniques, TRAMP mice were thentreated with placebo, flutamide (an antiandrogen; 33 mg/kg/day), or
toremifene(10 mg/kg/day). Animals from each treatment group were sacrificed at 7, 10, 15,20, 25, and 30 weeks
Men with non functionnal 5-alpha-reductase of age, and prostate tissues and seminal vesicles wereharvested. Tissues from animals (n = 5) in each group were
evaluated bywholemount dissections of genitourinary tracts, histology, immunohistochemistry,and Western blot
analyses. Blood was pooled per group to measure estradiol andtestosterone hormonal levels. Tumors formed at
week 17 in the placebo group (n =10), at week 21 in the high-dose toremifene group (n = 12), and at week 29
2 inthe low-dose toremifene group (n = 12). This represents an increased tumorlatency of up to 12 weeks. By 33
weeks, all animals in the placebo group hadtumors compared with only 35% of the animals treated with
toremifene. Althoughboth flutamide and toremifene decreased tumor incidence compared with theplacebo,
toremifene was more effective than flutamide. High-grade prostaticintraepithelial neoplasia was observed in
No Prostate cancer animals in the placebo group, but notin animals treated with toremifene. Moreover, toremifene-treated animals
hadprolonged survival compared with placebo-treated animals. By 33 weeks of age,100% of the placebo-treated
animals had developed palpable tumors and died,whereas 60% of the toremifene-treated animals were tumor free.
Ross RK, Pike MC, Coetzee GA, Reichardt JKV, Mimi CY, Feigelson H, Stanczyk FZ, Kolonel LN, T antigen levelsin the prostate of toremifene-treated animals were similar to those ofplacebo-treated, age-matched
Henderson BE. Androgen metabolism and prostate cancer: establishing a model of genetic animals. Whereas serum estradiol levels remainedunchanged, the total and free testosterone levels were elevated
in thetoremifene-treated group. Toremifene treatment did not affect androgen receptorlevels. Because toremifene
susceptibility. Cancer Res. 1998;58:44974504 prevented prostate cancer in a milieu of elevatedblood free testosterone levels with no change in prostate
androgen receptorexpression, the mechanism of toremifene's chemopreventive activity may bethrough
nonandrogenic pathways, such as estrogen receptor signaling.PMID: 11888907 [PubMed - indexed for MEDLINE]

Blocking estrogens => reduces 2-OH-estrone 16- -OH- estrone

prostate cancer metastasis => Prostate cancer risk
Trioxifene (LY133314) is a selective estrogen receptor modulator (SERM) with n = 113 men aged 45-85 yrs Highest Tertiles of Urinary
competitive binding activity against estradiol for estrogen receptor + prostate cancer;
alpha(ERalpha) & antagonistic activity against ERalpha-mediated gene 317 controls
expression. The PAIII rat prostatic adenocarcinoma (PCa) is an androgen 16-alpha-0H- 2-0H-
receptor-negative,ERalpha- and ERbeta-positive, spontaneously estrone estrone
metastatic rodent tumor cell line. After s.c. implantation of 10(6) PAIII cells in the 2-0H- +69 % 16-alpha-0H-
tail, s.c. administration of trioxifene (2.0, 4.0, 20.0, or 40.0 mg/kg-day) for 30
Lowest estrone
2 estrone
days produced significant (P < 0.05) inhibition of PAIII metastasis from the Prostate Tertile
1,5 RATIO
primary tumor in the tail tothe gluteal & iliac lymph nodes (max. nodal Cancer 1.69
weight decreases, 86% & 88%from control values, resp.). PAIII metastasis 1 -17 % (95% CI -39 %
to the lungs was sign. inhibited by trioxifene treatment. Numbers of
Risk
1 0.83 0.93-
pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by trioxifene 0,5 0.61
(95% CI: 3.06)
administration in a dose-related manner (maximal reduction, 98% from controlvalues). (0.33-1.15)
0 0.43-1.44)
Continual administration of the compound sign (P < 0.05) extended NS p = 0.02 p = 0.04
survival of PAIII-bearing rats. Trioxifene inhibited the proliferation of PAIII
Figure: The estrogen metabolic pathway favoring 2-hydroxylation over 16-alpha-
cells at micromolar levels in vitro but did not slow growth of the primary
hydroxylation may reduce risk of clinically evident prostate cancer.
tumor growth
Neubauer inAM,
BL, McNulty the tail.
Chedid Trioxifene
M, Chen administration
K, Goode RL, also
Johnson MA, Jones produced
CD, Krishnan regression
V, Lynch of Graff
R, Osborne HE, male
JR. The selective estrogen receptor modulator trioxifene (LY133314) inhibits metastasis and extends survival in the PAIII rat Muti P, et al. Urinary estrogen metabolites and prostate cancer: a case-control study in the
accessory sexmodel.
prostatic carcinoma organs.
CancerIn PAIII-tumor-bearing
Res. 2003 Sep 15;63(18):6056-62animals, trioxifene
Lilly Research Laboratories, administration
A Division of Eli Lilly and
United States. Cancer Causes Control. 2002 ;13(10):947-55 State University of New York
produced a maximal
Company, regression
LillyCorporate of 76% Indiana
Center, Indianapolis, for ventralprostate and 64% for seminal
46285, USA. neubauer_blake_l@lilly.com

Estrogen Metabolites
Enzymes : COMT
& Prostate cancer
Estrogen Mechanism: Deactivates the 4-OH
Ventral & anterior part: cancer incidence because of estrone & 2 0H-estrone
levels of Glutathion-S-Transferase (GST), NADPH- in methoxyestrogens
quinone reductases (NADPHR) & Catechol-O-Mthyl (anti-proliferative
Transferase(COMT) activity)
Ventro-posterior: cancer incidence because levels Methoxyestrogens
of GST,COMT,NADPHROne study in men : 113 men + inhibit on their turn
prostate cancer & 300 controls, measured 2-OH-estrone & CYP1B1 & CYP1A1
16-OH-estrone :
16-OH-estrone & 2-OH-estrone
Cancer Causes Control 2003, 13(10):947-55.

16
 Levels of 2 & 16 hydroxyestrogens: Therapeutic 2- or 16-OH-estrone
Therapeutic Modulation Modulation
CYP3A4 CYP1A1
Their respective concentrations are determined
by intracellular activity of Cytochrome P450, Inhibited Stimulated by
CYP1A1 gives 2 -OHestrone by grape fruit Cruciferous
vegetables
CYP3A4 produces 16-OH-estrone Epoxy Indole - 3- Carbinol
Beneficial clinical results is due to their induction bergamottine (by contact of gastric acidity
of phase II enzymes de conjuguation: GST & (300mg of grapefruit with rest it dimerises into DIM that
reducing to 40% CYP3A induces GST & NQR)
NADPH-quinone reductase activity )
Lignens
(flaxseed seeds)

Chrysin
Chrysin = chemical name for a type of
isoflavone molecule that has been
demonstrated to be a potent aromatazation
blocker.
=> minimizes the conversion of testosterone to
either estrogen or DHT (dihydrotestosterone).
Where does Chrysin come from?
Chrysin is extracted from a fairly rare plant
called the Passiflora Caerula. => natural extract
yet more powerful than most anti-aromatase
drugs you might be familiar with.
Chrysin
Studies done in Europe show that after
supplementing with chrysin blood serum levels
of testosterone went up a whopping 30%!
How does this work? Chrysin basically
estrogen levels by cutting down on its
conversion from testosterone.
500 mg per serving
1-3 grams of chrysin per day
= safe & effective dose.

DIM
= highly recommended for men + estrogens
DIM => the toxic effects to estrogen dominance.
"a 2-OH-estrone to 16-alpha-estrone ratio ( 2OH :
16-alpha) has been shown to be carcinogenic
DIM & eating cruciferous vegetables
specific aerobic metabolism for estrogen Extracts of cruciferous vegetables such as I3C
=> the chance for estrogen to be broken (indole-3-carbinole) & its more absorbable
metabolite DIM (di-indolyl-methane) apparently
down into its beneficial, or "good" estrogen improve this ratio thru up-regulation of the CYP1A2
metabolites. liver enzymes involved in the metabolism of
Good estrogen metabolites estrogens
(Cancer Lett 1997;114(1-2):169-170).
= 2-hydroxy estrogens.

17
 DIM
=> highly recommended for women + HRT or Genistein=> structure
at risk for breast cancer as it will the toxic
effects to estrogen dominance.

DIM => induce a favorable 2/16 ratio & induce

apoptosis in breast cancer cells (Biochem
Pharmacol 1999; 58(5):825-34, Carcinogenesis 1998;
19(9):1631-9)
I3C also improved 2/16 ratios & induced a
complete regression in 50% of patients with Figure 1. Structure of genistein.
cervical dysplasia of CIN II-III (Gynecol Oncol
2000;78(2):123-9).

Genistein=> prostate cancer

Genistein
Figure 7. Genistein reduces the
=> prostate incidence of mice with advanced
prostate tumors. The urogenital
cancer tract collected at necropsy was
prepared for pathological evaluation of
the prostate by established criteria (49
,50 ). The results are the % of mice in
each group with prostates displaying
poorly differentiated
adenocarcinomas; 2 test revealed
that the frequency of transgenic mouse
Figure 6. Prostate cancer incidence inHH Lobund-Wistar rats fed genistein in the diet. prostate adenocarcinoma (TRAMP)
Lobund-Wistar rats were provided 0, 25 and 250 mg genistein/kg AIN-76A diet starting mice with poorly differentiated
at conception. Male offspring were treated with 33 mg flutamide/kg body by gavage on adenocarcinomas decreased
5066 and injected with 25 mg testosterone/kg on d 6769; 42 mg methylnitrosourea/k significantly as a function of genistein
injected into the dorsolateral prostate on d 70; and 25-mg testosterone implants were in the diet (P = 0.041).
started on d 77 (and replaced every 12 wk). Animals were necropsied when 48 wk old [Data from (51 ). Permission granted
when moribund. aP = 0.04 compared with the AIN-76A diet group (Fisher exact test), from American Association for Cancer
and P = 0.03 by Cochran-Armitage trend test for tumor invasive adenocarcinomas. [Da Research.]
modified from (47 ). Permission granted from Elsevier Science Ireland.]

Xenoestrogens
Chemical derivatives such as organochlorinated
pesticides, dioxines, ethinyestradiol of birth contro
The
plill arrived in ground water => induce in vitro
estrogenic or carcinogenic effects similar to estrogens
They induce enzymes such as CYP1B1 => mutagenic
3,4-catcholestrogenes, modify the activity of CYP450
End
Pesticides the ratio 16/2 OHE2,1 ( replication)
By competitive inhibition of COMT, pesticides increase
the life duratoin of endogenous mutagenic
catecholestrogens

18