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. roberts.rosebud@mayo.edu

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. 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

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

• 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.

beert@ohsu.edu

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%