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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 menIncreased 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
=> intima-media thickness
in middle-aged men
g
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
0
20
40
60
80
100
120
140
160
estrone
estradiol
Plasma estrogens
(nmol/l) E1
Figure : the plasma levels of the estrogens are more elevated in men with myocardial infarction
Myocardial infarct
control
E2
Serum E1 & E2 levels in men with myocardial infarction
Gynecomastia= the development of abnormally
large mammary glands in males
=> resulting in breast enlargement.
http://en.wikipedia.org/wiki/Gynecomastia
γυνή gyne (stem gynaik-) meaning "woman"
•The term comes from the Greek and μαστός mastos meaning "breast".
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
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. [email protected]
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
Sign. higher (P < 0.0025) mean E2/free T ratio in PC patientsThe 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 effectsg
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
0
60
< 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
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
n = 32 men; median age, 60.9 years; follow-up for 12 years
Men
Mean
serum
bioavailable
testosterone
(ng/dL)
Serum bioavailable testosterone P = 0.001
Age
-30 %
Serum estradiol / bioavailable testosterone ratio
P = 0.04
-30 %53.850.2
41.20.440.42
0.50
Among men w/ bioav. Testo > median, estradiol levels had a dose response ass. w/
prostate size. Among men + bioav. Testo </= the median => no assoc.
Alcohol, caffeine => Men
0
50
100
150
200
Serum estradiol
Normal
Serum
level
in men
(%)
High
caffeine
( > 14
cups
/week)
+ 66%+59%
Serum hormone levels in 52 healthy Greek elderly men in function
of drinking and smoking.Figure:
Hsieh CC, Signorello LB, Lipworth L, Lagiou P, Mantzoros CS, Trichopoulos D. Predictors of sex
hormone levels among the elderly: a study in Greece. J Clin Epidemiol 1998 Oct;51(10):837-41
Alcohol
( > or = 7
glasses
/week)
Non
smoker
Serum
testosterone
Serum
DHEAs
- 37%- 27%
Current
smoking Non
smoker
Current
smoking
p < 0.05 p < 0.05 p < 0.05
Coffee => benign prostate hypertrophy
0,5
1
1,5
2
1 2 3 4 5 6
Men
treated
surgically
for BPH or
in
'watchful
waiting' for
surgical
intervention
Figure 2: Coffee constituents, which increase the serum
concentration of low-density lipoprotein cholesterol, may
be involved in the pathophysiology of BPH
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
n = of 882 men (aged 65, 70, 75 & 80 years)
Sign.
Positive
association
Cups/day
of Coffee
Figure 1: The prevalence
of surgery for BPH
increased with age
0
10
20
30
40
50
Prevalence
of
surgery
for BPH 41 %
Men
(aged
65)
Men
(aged 90 yrs)
15 %
Smoking => serum E2 (& testo)
0
10
20
30
40
Serum
Estradiol
(pg/mL)
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.
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.
P < 0.01
n = 68 men + BPH (mean age 59 years, range 52-74)
Men with benign prostate hypertrophy
SmokersNonsmokers
26.7
pg/ml
33.8
pg/ml
Obesity => serum E2
0
10
20
30
40
50
60Serum
Estradiol
(pg/mL)
Fig.: Average specimen weights increased with increasingly obesity &
increasing host age from 46 to 80 g.
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.
P < 0.01
n = 68 men with benign prostatic hyperplasia
Men with benign prostate hyperplasia
younger than 60 yrs
Obese > or = 140 %
recommended weight
Underweight
26.8
pg/ml
52,3
pg/ml
The serum oestradiol was sign. elevated in
obese men who were 140% or over recommended weight vs underweight men
younger than 60 yrs.
Estradiol in obese persons
Abundant hormone in men
Oettel M, Mukhopadhyay AK. Progesterone: the forgotten hormone in men? Aging
Male. 2004 Sep;7(3):236-57
0
20
40
60
Figure: Sign. elevated the serum
oestradiol level in obese men .
Average prostate specimen
weights increased with
increasingly obesity & increasing
host age from 46 to 80 g.
Soygur T, Kupeli B, Aydos K, Kupeli S, Arikan N, Muftuoglu YZ. Effect of obesity on prostatic
hyperplasia: its relation to sex steroid levels. Int Urol Nephrol.1996;28(1):55-9. Un. Ankara, Turkey
Serum
Estradiol
(pg/ml)
n = 68 men + benign prostatic hyperplasia
26.8
51.3
Underweight
men younger
> 60 yrs
Obese men
= or > 140% over
recommended
weight
The degree of obesity has a direct
effect on oestradiol levels through
transformation of androgens in
adipose tissue to oestrogens.
Despite the larger adenomas, no
increase in the symptom score for
BPH was observed with
increasing obesity.
Varicocoele
Varicocele
Varicocele => Sign. E2 after HCGcorrected after varicocelectomy
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.
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 steroidSign. 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.
Varicocele: low testo & progesterone/17-OH-P
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.
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
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
Tabs of 1 mg
Dosis for men: 2 x1/4 tab/week to ½ tab/day
LETROZOLE:
Tabs of 2.5 mg
Dosis for men: 2 x1/4 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-dominant environments. Estrogens are key hormones for the induction and the development of BPH.
Suzuki K, Inaba S, Takeuchi H, Takezawa Y, Fukabori Y, Suzuki T, Imai K, Yamanaka H, Honma S. [Endocrine environment of benign prostatic hyperplasia--relationships of sex steroid hormone
levels with age and the size of the prostate] Nippon Hinyokika Gakkai Zasshi. 1992 May;83(5):664-71. Division of Urology, Shakai Hoken Mishima Hospital.
Aromatse inhibitor
=> E => prostate sizeestrogens 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 & sign. prostatic volume.Schweikert HU, Tunn UW, Habenicht UF, Arnold J, Senge T, Schulze H, Schroder FH,Blom
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. [email protected] 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
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. [email protected]
• 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).
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 (aromatase inhibition)
=> testosterone levels, estradiol levels, appears to BMD
g
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,
40
1 tab/day Anastrozole not good for the arteries
STUDY: placebo-controlled double-blind randomized designSUBJECTS: 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 healthy men
Lew R, Komesaroff P, Williams M, Dawood T, Sudhir K.Baker Endogenous estrogens influence endothelial function in young men. Circ Res. 2003 Nov 28;93(11):1127-33. Epub 2003 Oct 30. Medical Research Institute and Alfred
Hospital, Prahran, Victoria,Australia.
Memory performance improved with estradiol therapy but did not change in the 2 control groups => in men with prostate cancer
g
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.
Reduce estradiol but not too much => because higher risk of higher stage prostate cancerSUBJECTS: 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.
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.
Too high or too low serum E2 => increased mortality in men
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 baldnessMale-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 whichtestosterone 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%