How to reduce high

levels of estradiol
in men?

Thierry Hertoghe, MD
 Adverse effects of
high estradiol levels
in men
 Adverse effects of
high estradiol levels
in men
Increased risks of
1. Premature atherosclerosis
2. Myocardial infarction
3. Prostate hypertrophy
4. Prostate cancer
5. Gynecomastia
6. Erctile dysfunction, reduced fertility
  Serum total & free E2 levels
at baseline
g

=>  intima-media thickness

in middle-aged men

Tivesten A, Hulthe J, Wallenfeldt K, Wikstrand J, Ohlsson C, Fagerberg B. Circulating estradiol is an

independent predictor of progression of carotid artery intima-media thickness in middle-aged men.
J Clin Endocrinol Metab. 2006 Nov;91(11):4433-7
  Serum E1 & E2 levels in men
with myocardial infarction
Myocardial infarct
Plasma 160
140
estrogens 120 control estrone
100 estradiol
(nmol/l) 80 E1
60
40 E2
20
0

Figure : the plasma levels of the estrogens are

more elevated in men with myocardial infarction
Gynecomastia
= the development of abnormally
large mammary glands in males

=> resulting in breast enlargement.

•The term comes from the Greek and μαστός mastos meaning "breast".

γυνή gyne (stem gynaik-) meaning "woman"

http://en.wikipedia.org/wiki/Gynecomastia
 Gynecomastia => sign.  E2 in all,
Gynecomastia puberty and primary or
secondary hypogonadism : sign. 
testosterone/E2, even if E2 within ref. limits

SUBJECTS: 91 men with gynaecomastia; control group

FINDINGS: sign.  Oestradiol-(E2) levels in serum than in control sp.

 Patients with testicular tumour, hyperprolactinaemia and

idiopathic gynaecomastia had highest E2 levels.

 Patients with gynaecomastia of puberty and primary or secondary

hypogonadism, the E2 level was within normal limits, but sign. 
testosterone/oestradiol ratio
Eversmann T, Moito J, von Werder K. [Testosterone and estradiol levels in male gynecomastia.
Clinical and endocrine findings during treatment with tamoxifen]. Dtsch Med Wochenschr. 1984
Nov 2;109(44):1678-82.
 Estradiol/low bioavailable Testo =>
 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
Sign. higher (P < 0.0025) mean
E2/free T ratio in PC patients
The PC patients
 highly sign. (P < 0.0005) lower mean E2 than in
the BPH patients.
 slightly lower (P < 0.05) mean free T & mean
E2/free T ratio than the BPH patients.
 Sign. higher (P < 0.0025) mean E2/free T
ratio, which was also sign. higher in the BPH
patients (P < 0.0005)

Rannikko S, Adlercreutz H. Plasma estradiol, free testosterone, sex hormone binding globulin
binding capacity, and prolactin in benign prostatic hyperplasia and prostatic cancer. Prostate.
1983;4(3):223-9.
Estrogens for prostate cancer =>
deleterious
g effects

Guidlelines 2009 of the European association of Urology

 How to reduce high levels
of estradiol in men?

1. Stop alcohol & caffeinated beverages & foods;

stop smoking
2. Wear loose (not tight) underwear
3. Loose overweight
4. Removal of varicocele
5. Take aromatase inhibitors or stimulators of
the conversion of E2 into E1
Age => increasingly  E2:testo ratio
Men
Serum bioavailable testosterone
Mean P = 0.001
60 53.8 -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
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
Alcohol, caffeine => Men
Serum Serum estradiol Serum Serum
level testosterone DHEAs
High Alcohol
in men caffeine ( > or = 7
(%) ( > 14 glasses
200 cups /week) Current Current
/week) Non smoking Non
150
smoking
Normal +59% + 66% smoker smoker
- 27%
100 - 37%

50

0
p < 0.05 p < 0.05 p < 0.05
Figure: Serum hormone levels in 52 healthy Greek elderly men in function
of drinking and smoking.
Hsieh CC, Signorello LB, Lipworth L, Lagiou P, M antzoros CS, Trichopoulos D. Predictors of sex
hormone levels among the elderly: a study in Greece. J Clin Epidemiol 1998 Oct;51(10):837-41
Coffee =>  benign prostate hypertrophy
2
Prevalence Men
of 50
(aged 90 yrs) Men Sign.
surgery treated Positive
40
for BPH surgically 1,5
association
41 %
30 Men for BPH or
(aged in
20 65) 'watchful
1
waiting' for
10 15 %
surgical
intervention
0
0,5

1 2 3 4 5 6
Cups/day
of Coffee
Figure 1: The prevalence Figure 2: Coffee constituents, which increase the serum
of surgery for BPH concentration of low-density lipoprotein cholesterol, may
increased with age be involved in the pathophysiology of BPH
n = of 882 men (aged 65, 70, 75 & 80 years)

Klag MJ, Mead LA, LaCroix AZ, Wang NY, Coresh J, Liang KY, Pearson TA, Levine DM. Coffee intake and
coronary heart disease. Ann. Epidemiol. 1994;4(6):425-33 , Johns Hopkins University, Baltimore
Smoking =>  serum E2 (&  testo)
Men with benign prostate hypertrophy

Nonsmokers Smokers
40

Serum 30
Estradiol
20 26.7 33.8
(pg/mL) pg/ml pg/ml
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)
Küpeli B, Soygür T, Aydos K, Ozdiler E, Küpeli S. The role of cigarette smoking in prostatic enlargement.
Br J Urol. 1997 Aug;80(2):201-4. SSK Diskapi Hospital, Ankara, Turkey.
Obesity =>  serum E2
Men with benign prostate hyperplasia
younger than 60 yrs
Underweight Obese > or = 140 %
recommended weight
60
Serum 50 52,3
Estradiol 40 pg/ml
30
(pg/mL) 20 26.8
10 pg/ml
0
P < 0.01
Fig.: Average specimen weights increased with increasingly obesity &
increasing host age from 46 to 80 g. The serum oestradiol was sign. elevated in
obese men who were 140% or over recommended weight vs underweight men
younger than 60 yrs. n = 68 men with benign prostatic hyperplasia

Küpeli B, Soygür T, Aydos K, Ozdiler E, Küpeli S. The role of cigarette smoking in prostatic enlargement.
Br J Urol. 1997 Aug;80(2):201-4. SSK Diskapi Hospital, Ankara, Turkey.
 Estradiol in obese persons
Obese men Figure: Sign. elevated the serum
= or > 140% over oestradiol level in obese men .

Abundant
60
hormone in recommended
weight
Average prostate specimen
weights increased with

Serum men Underweight

men younger 51.3
increasingly obesity & increasing
host age from 46 to 80 g.
Estradiol 40 > 60 yrs
The degree of obesity has a direct
(pg/ml) effect on oestradiol levels through
26.8
20 transformation of androgens in
adipose tissue to oestrogens.
Despite the larger adenomas, no
0 increase in the symptom score for
BPH was observed with
n = Oettel
68 menM,+ Mukhopadhyay
benign prostatic hyperplasia
AK. Progesterone: the forgotten hormone in men? Aging
increasing obesity.
Male.S,
Soygur T, Kupeli B, Aydos K, Kupeli 2004
ArikSep;7(3):236-57
an N, Muftuoglu YZ. Effect of obesity on prostatic
hyperplasia: its relation to sex steroid levels. Int Urol Nephrol.1996;28(1):55-9. Un. Ank ara, Turk ey
Varicocoele
Varicocele
 Varicocele => Sign.  E2 after HCG
corrected after varicocelectomy

PATIENTS: 6 male adolescents 15 to 19 years of age with bilateral gynecomastia and visible
varicoceles.
INTERVENTION: human chorionic gonadotropin (hCG) 2,000 IU for 3 consecutive days
before and 3 months after varicocelectomy.
RESULTS: Varicocelectomy
No significant changes in the basal (pre-hCG) levels of the steroid
Sign.  testosterone levels with hCG (P <0.005) higher after varicocelectomy (before T, 925 ng%;
after T, 1,649 ng%).
Sign. stimulated levels of estradiol and androstenedione A (P <0.005) after varicocelectomy (E2,
62 +/- 12 pg/mL; A, 326 ng% +/- 80 ng%) than before (E2, 106 +/- 13 pg/mL; A, 580 ng% +/-
95 ng%).
CCL: The reciprocal effect on the levels of T and its immediate precursor, A, suggests an
impairment of the 17-ketoreductase enzyme activity. The increased levels of E2 after hCG
and its normalization after varicocelectomy suggests that varicoceles may play a
pathogenetic role in the development of gynecomastia.

Castro-Magana M, Angulo M, Uy J. Elevated serum estradiol associated with increased

androstenedione-testosterone ratio in adolescent males with varicocele and gynecomastia. Fertil
Steril. 1991 Sep;56(3):515-8.
 Varicocele: low testo &
progesterone/17-OH-P
SUBJECTS: 34 varicocele patients & 13 normal subjects
RESULTS:
• sign. lower testosterone (T) & delta 4 in the spermatic blood of
varicocele (V) patients
• A negative correlation between the individual age of varicocele
patients & 17-OH-P (No. 34, y =-30.66x + 1300, r = -0.57, P < 0.01)
delta 4 values (No. 27, y = -1.981x+ 96.52, r = -0.67, P < 0.01).
• a positive correlation between the P/17-OH-P ratio & age of
varicocele (No. 33, y = 0.0065x-0.092, r = 0.45, P < 0.03)
• The positive correlation between the P/17-OH-P ratio and age of
varicocele patients (n = 28,y = 0.007 x -0.090, r = 0.45, P < 0.03)
suggests a progressive impairment of 17-alpha-hydroxylase in such
patients as they grow relatively older

Ando S, Giacchetto C, Colpi GM, Beraldi E, Panno ML, Sposato G. Testosterone precursors in spermatic
venous blood of normal men and varicocele patients. A study of delta 4 pathway of testosterone
biosynthesis. Acta Endocrinol (Copenh). 1985 Feb;108(2):277-83; Ando S, Giacchetto C, Beraldi E, Panno ML,
Carpino A, Brancati C. Progesterone, 17-OH-progesterone, androstenedione and testosterone plasma levels
in spermatic venous blood of normal men and varicocele patients. Horm Metab Res. 1985 Feb;17(2):99-103.
Progesterone

Aim: reduce excessive estradiol levels

By converting estradiol to the 3 to 10 x
less potent estrone
PROGESTERONE:
 Tabs of 100 mg

 Dosis for men: 1 caps /day => -30 %  serum estradiol

 Before bedtime and after sex

Aromatase Inhibitors

Aim: reduce excessive estrogen levels

Examples: Arimidex® (anastrozole)
ANASTROZOLE LETROZOLE:
 Tabs of 1 mg  Tabs of 2.5 mg

 Dosis for men: 2 x1/4  Dosis for men: 2 x1/4

tab/week to ½ tab/day tab/week to ½ tab/day

Aromatase inhibitors:
Doses for men

Arimidex® (anastrozole): very small doses:

¼ per week to ½ per day
as it can be very (too) potent in many men

Mean dose: 3x ¼ per week

EStrogen depletion =>  prostate size
SUBJECTS: healthy 154 men, ages from 18 to 91 years old.
In 59 men, prostatic size was estimated by digital
examination & 3 groups: < or= to walnut size, small hen's
egg size & = to or larger than hen's egg size.
RESULTS:
• a slight decrease in Total-T over 60years old, a significant
decrease in Free-T, and no change in E2 with age. E2/Total-
T & E2/Free-T ratio increased sign. after middle-age.
• Inthe larger prostate group, a sign. lower Total-T & sign.
higher E2. But there was no difference in Free-T.
• the prostatic size was correlated positively with E2
level,E2/Total-T & E2/Free-T ratio.
CCL: the endocrine environment tended to be estrogens-
dominant with age, in particular, after middle-age, & that
patients with large prostates have more estrogens-
Suzuki K, Inaba S, Takeuchi H, Takezawa Y, Fukabori Y, Suzuki T, Imai K, Yamanaka H, Honma
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.
 Aromatse inhibitor
=>  E =>  prostate size
estrogens 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), a newly developed aromatase inhibitor, in men with BPH.
STUDY: open multicenter study 49 men (mean age 70.1years, range 55 to
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
patients discontinued the study for reasons unrelated to treatment.
RESULTS: With treatment BPH-related symptoms such as daytime voiding
frequency, nycturia, peak flow & residual urine improved considerably;
however, these parameters did not reach statistical significance. The mean
prostatic volume decreased significantly from 74.2 +/- 31.7 to 64.0 +/- 31
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
& Schweikert
sign. HU, Tunn UW, Habenicht UF, Arnold J, Senge T, Schulze H, Schroder FH,Blom
prostatic volume.
JH, Ennemoser O, Horniger W, et al. Effects of estrogen deprivation on human benign
prostatic hyperplasia. J Steroid Biochem Mol Biol. 1993 Mar;44(4-6):573-6. Department of
Internal Medicine, University of Bonn, Germany.
An anti-estrogen blocks prostate
cancer growth in mice while
increasing testo levels
 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 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 mg/kg/day);(b) the high-
dose toremifene group (33 mg/kg/day); and (c) the control placebogroup. Efficacy of 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 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 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 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. T antigen levelsin the prostate
of toremifene-treated animals were similar to those ofplacebo-treated, age-matched 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 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 =>
 prostate cancer metastasis
• Trioxifene (LY133314) = selective estrogen receptor modulator (SERM) with
competitive binding activity against E2 for estrogen receptor alpha
(ERalpha) & antagonistic activity vs ERalpha-mediated gene expression.
• PAIII rat prostatic adenocarcinoma (PCa) = androgen receptor-
negative, ERalpha- & ERbeta-positive, spontaneously metastatic
rodent tumor cell line.
RESULTS: After s.c. implant of 106 PAIII cells in tail, s.c. trioxifene for 30 days
=>sign. (P < 0.05)  PAIII metastasis from the primary tumor in the tail
• to the gluteal & iliac lymph nodes (max. nodal weight , -86% & -88%
from control values, resp.).
• to the lungs: sign. (P < 0.05)  numbers of pulmonary foci in PAIII-bearing
rats in a dose-related manner (maximal reduction, 98% from controlvalues).
=> Continual Therapy=>  survival of PAIII-bearing rats. (P < 0.05)
=> Trioxifene  the proliferation of PAIII cells at µmolar levels in vitro
but did not slow growth of the primary tumor growth in the tail.
• regression of male accessory sex organs => maximal regression of -
76% for ventral prostate & -64% for seminal vesicle (P < 0.05 for both).
Neubauer BL, McNulty AM, Chedid M, Chen K, Goode RL, Johnson MA, Jones CD, Krishnan V, Lynch R, Osborne HE, Graff JR.
The selective estrogen receptor modulator trioxifene (LY133314) inhibits metastasis and extends survival in the PAIII rat
prostatic carcinoma model. Cancer Res. 2003 Sep 15;63(18):6056-62 Lilly Research Laboratories, A Division of Eli Lilly and
Company, LillyCorporate Center, Indianapolis, Indiana 46285, USA. neubauer_blake_l@lilly.com
Estrogen receptor
blockers

Aim: block excessive estrogen recpetors

Examples: Novaldex® (tamoxifen)
TAMOXIFEN:
 Tabs of 10 to 20 mg

 Dosis for men:

5-10 mg/day
 Tamoxifen=>  Gynecomastia

SUBJECTS: 16 men with gynaecomastia

FINDINGS: sign.  Oestradiol-(E2) levels in serum than in controls
TREATMENT: Tamoxifen, at a daily dose of 20 mg over 2-4 months
 Of 12/16 patients with painful gynaecomastia ten became painfree
 Gynaecomastia regressed partially or completely in 14/16
patients, in only 2 was it unchanged.
 no recurrence of gynaecomastia after discontinuing tamoxifen.
 Side-effects did not occur.
CCL: tamoxifen = alternative to the surgical treatment of gynaecomastia

Eversmann T, Moito J, von Werder K. [Testosterone and estradiol levels in male

gynecomastia. Clinical and endocrine findings during treatment with tamoxifen].
Dtsch Med Wochenschr. 1984 Nov 2;109(44):1678-82.
Do not excessively block
or reduce estrogens

!
 Aromatase inhibitors &
estrogen receptor blockers:
avoid excessive dosing in men

As estrogens are necessary in men:

For
- to stimulate the brain,including increasing libido
- To increase bone density
- To increase muscle mass
 In older men, Arimidex
g (aromatase inhibition)

=>
 testosterone levels,
 estradiol levels,
appears to  BMD
 Men > 50 years old, TT was not
indicative of osteoporosis risk
while E2 < 37 ng/mL was.,
FT < 7 ng/dL & BT < 180 ng/dL
Clapauch R, Mattos TM, Silva P, Marinheiro LP, Buksman S, Schrank Y. Total estradiol,
rather than testosterone levels, predicts osteoporosis in aging men. Arq Bras Endocrinol
Metabol. 2009 Nov;53(8):1020-5.
Divisão de Endocrinologia Feminina e Andrologia, Setor de Endocrinologia,
1 tab/day Anastrozole not good for the arteries
STUDY: placebo-controlled double-blind randomized design
SUBJECTS: 20 healthy young men, aged 18 to 32 years, +
aromatase inhibitor anastrozole (1mg) or placebo. Endothelial
function => flow-mediated dilation of the brachial artery
RESULTS: after 6 wks of aromatase inhibition treatment (vs
baseline)
 Sign.  serum E2 from 85.4 pmol/L (23.6 pg/mL) to 64.3 pmol/L
(17,5 pg/mL) (P=0.042)
 sign.  flow-mediated dilation in subjects + anastrozole median,
6.1% (range, 5.2 to 13.4) to 3.5% (2.0 to 5.7), P=0.034] but not
in the placebo group
 in either the anastrozole or placebo group: No changes in nitroglycerin-
induced endothelium-indep. dilation; no change in systemic arterial
compliance; no sign. changes in lipoproteins, testosterone, DHEA, CRP,
or homocysteine levels
CCL: suppression of endogenous estrogens + aromatase inhibitor
=> impairment of flow-mediated dilation without sign.changes
in lipoproteins, homocysteine, or CRP. Endogenous estrogens
=> direct regulatory role in endothelial function in young
Lew R, Komesaroff P, Williams M, Dawood T, Sudhir K.Baker Endogenous estrogens influence endothelial function
in healthy men
young men. Circ Res. 2003 Nov 28;93(11):1127-33. Epub 2003 Oct 30. Medical Research Institute and Alfred
Hospital, Prahran, Victoria,Australia. 40
g

Memory performance improved with

estradiol therapy but did not
change in the 2 control groups =>
in men with prostate cancer
Beer TM, Bland LB, Bussiere JR, Neiss MB, Wersinger EM, Garzotto M, Ryan CW,
Janowsky JS.Testosterone loss and estradiol administration modify memory in men. J
Urol. 2006 Jan;175(1):130-5.Department of Medicine, Division of Hematology and
Medical Oncology, OregonHealth and Science University, Portland, Oregon, USA.
beert@ohsu.edu
Reduce estradiol but not too much
=> because higher risk of
higher stage prostate cancer
SUBJECTS: 238 patients (Finnprostate 6 study).
FINDINGS:
 The E2 & fE2 levels => sign. higher in M0 patients than in M1 patients
 no sign. dff. in T and fTlevels.
 In multivariate analyses, a decline in performance status (PS)
 increase in eruthorcyte sedimentation rate => related to a decrease in
T, fT, E2, orfE2 levels.
CCL: : Pretreatment plasma estradiol was significantly lower inM1 patients
than in M0 patients

Mikkola AK, Aro JL, Rannikko SA, Salo JO. Pretreatment plasma testosterone and estradiol levels
in patients with locally advanced or metastasized prostatic cancer. FINNPROSTATE Group.
Prostate. 1999 May 15;39(3):175-81.Department of Surgery, Helsinki University Central Hospital,
Finland.
 Reduce estradiol but not too much
because lower survival in prostate
cancer patients
Survival was particularly poor in the group
treated by orchiectomy with the lowest E2
values and statistically sign. different (P less
than .05) from that of the corresponding
grouptreated by estrogens

Haapiainen R, Rannikko S, Adlercreutz H, Alfthan O. Correlation of pretreatment plasma

levels of estradiol and sex-hormone-bindingglobulin-binding capacity with clinical stage
and survival of patients with prostatic cancer. Prostate. 1986;8(2):127-37.
 Too high or too low serum E2 =>
increased mortality in men
g

Figure 1. Serum Estradiol by Log Relative Hazard of Death Using Cubic Splines With 5 Knots During 3-Year
Follow-up in Men With Chronic Heart Failure and Reduced Left Ventricular Ejection Fraction
Serum estradiol by log relative hazard of death was calculated by using restricted cubic splines with 5 knots with
95% confidence intervals (dashed curves). To convert serum estradiol to pmol/L, multiply by 3.671.

JAMA. 2009;301(18):1892-1901
5-alpha-reductase
Inhibitors

Aim: reduce excessive

dihydrotestosterone levels
Examples: Proscar® (finasteride,
dutasteride)
 Adverse effects of
high dihydrotestosterone
levels
in men
Increased risks of
1. Male pattern baldness
2. Hirsutism (excessive body hair growth)

DHT does not promote prostate cancer, not

does it promote heart disease
Higher DHT in premature baldness
Male-pattern baldness (MPB) is not started from occipital, but frontal or
scalp of head. We can assume that distribution of androgenic steroids
is different for each region of the head.
SUBJECTS: 22 subjects + baldness, 13 + non-baldness
RESULTS:
 The level of dihydrotestosterone (DHT) & the ratio of testosterone to
epitestosterone(T/E ratio) in vertex hair from premature baldness
subjects were higher than in the sample of non-baldness subjects
(P<0.001, 0.001), whereas the levels of androgens in occipital hair
from the same baldness group were not different.
 the levels of DHT, testosterone, & DHT/T ratio in plasma from
premature MPB were higher than in those of control subjects(P<0.001,
0.001, 0.005).
 CCL:

 the distribution of androgenic steroids is unlike in various regions of

individual subjects.
 the increased DHT/T ratio in balding plasma indirectly confirms the
high activity of 5alpha-reductase type II.
Bang HJ, Yang YJ, Lho DS, Lee WY, Sim WY, Chung BC. Comparative studies on level of
androgens in hair and plasma with premature male-pattern baldness. J Dermatol Sci. 2004
Feb;34(1):11-6. Bioanalysis and Biotransformation Research Center, Korea Institute of Science
and Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea.
Finasteride

= progesterone derivative
 Finasteride:
Efficient doses
Oral: 2-2.5 mg/day

Only to administer if simultaneous

testosterone treatment
(even 1 mg/day (Propecia® should only
begiven with co-administration with
 Adverse effects of
excess finasteride
(without testosterone)
in men
At ≥ 1 mg/day without protective testosterone treatment:
1. Excessive levels of estradiol
2. Deficient levels of dihydrotestosterone
1. Atrophy of genital areas in men => Erectile dysfunction,
ejaculation decrease
2. Testicular inflammation
3. Hyperchondriac reactions, anxiety, depression, suicidal ideas
At ≥ 5 mg/day without protective testosterone treatment:
1. Rare cases of stroke
2. Increase in risk of aggressive prostate cancer (against which
testosterone is protective)
 How to avoid
Adverse effects of
finasteride?

1. Avoid given an excessive dose (> 2-2.5 mg/day)

2. Avoid by
adding a sufficient amount of testosterone:

50 mg/day of transdermal testosterone

for 2.5 mg/day of finasteride)
 TREATMENT doses

 Testosterone transdermal gel, liposoam

systemic use

Testosterone gel 10%