hypogonadism

Déficit de Testoterona

Eduard García CruzUrología y Salud del Hombre

Servicio de UrologíaBarnaclínic

Hospital Clínic de Barcelonaecruz@clinic.ub.es

@drgarciacruzwww.reisho.com

Conflict of interest: he recibido fondos para investigación de BAYER, Lilly, Pfizer, Auxilium y Janssen, he formado parte de comités asesores para Bayer, Lilly, Gebro, Almirall, Janssen, Italpharmaco y Menarini. Soy ponente para Lilly, Pierre Fabre y Bayer.

Fisiología de la testosterona

GnRH(hipotálamo)

LH(hipófisis)

FSH(hipófisis)

Testosterona (células de Leydig)

Espermatogénesis(células de Sertoli)

Hipogonadismo primarioHipogonadismo secundario

T

DHT

5- -reductasaɑ(finasteride, dutasteride)

Morley JE. Metabolism 46(4) 1997:410-3

Harman SM J Clin Endocrinol Metab 86 (2) 2000: 724-731 Leifke Clin Endocrinol 53 2000: 689-695

Estado de ánimo (mood)Libido

Masa grasa/Masa magra

Vellosidad/Gl seborreicas

ProducciónEPO

Sterm Cells

Producciónproteínas

séricas

ErecciónPróstata

Espermatogénesis

MetabolismoÓseo

TDS: definición, clínica y diagnóstico

“Tempus irrefutabile fugit” Virgilio

Testosterona > 346 ng/dL

Testosterona 231 – 346 ng/dL

Testosterona < 231 ng/dL

Total TestosteroneFree TestosteroneSHBGLHProlactin

Total Testosterone >346ng/dLLow calculated testosterone

Total Testosterone 231-346ng/dL

Total Testosterone <231ng/dL

Total Testosterone >346ng/dLNormal calculated testostosterone

Confirm results:

Total TestosteroneFree TestosteroneSHBG 2nd low free testosterone

2nd total T 231-346

TESTOSTERONETREATMENT

NO TESTOSTERONE

TREATMENT

García-Cruz E, ESSM Newsletter 2010.

3. Prevalencia y etiología.

PREVALENCIA Y FACTORES DE RIESGO DEL S ÍNDROME DE DEFICIENCIA DE TESTOSTERONA.

García-Cruz E, García Larrosa A, Franco de Castro A, Alcaraz Asensio A. Hospital Clínic de Barcelona-

Introducción: el síndrome de deficiencia de testosterona (TDS) es una entidad clínica y bioquímica que puede alterar múltiples órganos y sistemas, y que puede deteriorar la calidad de vida. La prevalencia de TDS en mayores de 50 años es de 10%, aumentando hasta el 25-30% en mayores de 70 años.

Objetivo: conocer la incidencia de TDS en nuestra población y la comorbilidad asociada.

Material y Métodos: análisis prospectivo de los 469pacientes consecutivos sometidos a biopsia transrectal de próstata durante el periodo entre Junio de 2007 y Diciembre de 2008 en el Hospital Clínic de Barcelona. Tras la biopsia transrectal de solicitó analítica hormonal a los pacientes, incluyendo Testosterona, LH, SHBG y DHT. La determinación se realizó en ayunas entre las 7h00AM y las 11h00AM. Se analizaron prospectivamente edad, peso, talla, IMC, hábitos tóxicos y antecedentes patológicos. Se utilizaron los valores de testosterona recomendados por la ISA-ISSAM-EAU para el diagnóstico de TDS, 231 y 346 ng/dL.

Resultados: Edad media 66,33±10,98 años. Testosterona media 448±168 ng/dL. Tasa TDS (Testosterona <231ng/mL) 7,5%. Tasa TDS (Testosterona <346 ng/dL) 28%. Tasa de TDS: <50 años TDS231 0% TDS346 20%; 50-60 años TDS231 7,8% TDS 346 24,7%; 60-70 años TDS231 7,4% TDS346 31,1%, 70-80 años TDS231 8,1% TDS346 27,9% y >80 años TDS231 7,1% TDS346 28,5%. En el análisis univariante, las variables IMC (p=0,007), HTA (p=0,027), Dislipemia (p=0,000) e Infección por VIH/VHC (p=0,000) correlacionaron con el nivel de testosterona sérica. En el análisis multivariante, las variables IMC (p=0,005) y Dislipemia correlacionaron con el nivel de testosterona sérica (465±171 ng/dL testosterona en pacientes sin dislipemia vs384±136 ng/dL testosterona en pacientes con dislipemia, p=0,002). En el análisis univariante, las variables Dislipemia (p=0,031), Insuficiencia Renal (p=0,018) y Antecedente de Trasplante (p=0,037) correlacionaron con la presencia de TDS (Testosterona<346ng/dL). En el análisis multivariante, la variable Dislipemia correlacionó con la presencia de TDS (Testosterona<346ng/dL) (23,1% en pacientes sin dislipemiavs 42,2% en pacientes con dislipemia, p=0,002).

Conclusiones: La tasa de TDS es de entre el 7,5 y el 28% en función del valor de corte. La dislipemiarepresenta un factor de riesgo para el TDS. La dislipemia y el IMC correlacionaron con los niveles de testosterona.

10 % de los hombres >50 años20 % de los hombres >60 años

Araujo et al. J Clin Endocrinol Metab 2004;89:5920-5960

25-30 % de los hombres >70 añosVermeulen. Ann Endocrinol 2003;64:109-114

11,5 % de hombres entre 60-90 añosWu et al –estudio EMAS- I J Androl 2005;28 (Suppl. 1):36

<231 <346

<50 0 20

50-60 8 25

60-70 7 31

70-80 8 28

>80 7 28

total 7 28

•Edad

•Enfermedades crónicas: Diabetes Mellitus, Enfermedad Pulmonar Obstructiva

Crónica, Enfermedades Inflamatorias Sistémicas, Insuficiencia Renal Crónica, Infección

crónica por VIH, Insuficiencia Hepática.

•Obesidad

•Farmacológico: corticoides, inmunosupresores, 5ARI, castración química.

•Patología testicular

Relación D2:D4, testosterona y sd. Relación D2:D4, testosterona y sd. de deficiencia de testosterona.de deficiencia de testosterona.

Eduard García-CruzEduard García-Cruz, Huguet Pérez J,, Huguet Pérez J, Pérez Márquez M, Piqueras Bartolomé M, Alcaraz APérez Márquez M, Piqueras Bartolomé M, Alcaraz A

Hospital Clínic de BarcelonaHospital Clínic de Barcelona

D2D4

♂ D4 > D2

D4 D2

♀ D4 ≤ D2

Testosterone (ng/dL)125010007505002500

Rat

io D

2:D

4

1,150

1,100

1,050

1,000

0,950

0,900

0,850

TDS (Testosterone >346 ng/dL)T<346T>346

Rat

io 2

D:4

D

1,100

1,050

1,000

0,950

0,900

76

3422

La Testosterona es más baja a medida que la relacióníndice/anular aumenta.

Relación entre T y D2:D4, B -741, ß -0,165, p=0,045 T<346 ng/dL 0,993±0,043 vs T>346 ng/dL 0,979±0,037, p=0,049

Resultados:

2D>4D2D<4D

Test

oste

rone

(ng/

dL)

1000

800

600

400

200

0

122

168

D2<D4 476±185 vs D2>D4 404±158, p=0,017

0%

10%

20%

30%

40%

50%

D2>D4 D2<D4

Prevalencia TDS

D2>D4 TDS 41.7% vs. D2<D4 TDS 23%, p=0.013

Los varones con D2≥D4 tienen menor Testosterona y mayor incidencia de TDS.

Conclusiones:

1. La ratio D2/D4 está relacionada con los niveles de testosterona.

2. La testosterona es mayor en aquellos pacientes con ratios D2:D4 bajos.

3. Los varones con D2>D4 presentan mayor riesgo de TDS.

4. Esta relación podría indicar una predisposición congénita a sufrir TDS.

4. Fisiopatología.

Men with higher levels of bioavailabletestosterone had better scores…

…low estradiol and high testosterone levels predicted better performance onseveral tests of cognitive function.

“…higher levels of bioavailable testosterone, but not ofbioavailable estradiol, are associated with better cognitivefunction in older men. “

“In addition, bioavailable measuresof testosterone may better reflect hormone levels availableto the brain and thus be more closely associated with centralnervous system outcomes such as cognition.”

“Hypogonadal men showed an increased incidence of depressive illness and a shorter time to diagnosisof depression.”

“The mean score on the test increased after 12 weeks’treatment with testosterone by an average of 32.6%...”

.

“This confirms that the effects of testosterone on spatial cognition are not mediated by estradiol. However, the precise mechanism by which testosterone enhances spatial cognition is not known.”

“…benefited both psychological aspects of depression(such as depressed mood, guilt and psychologicalanxiety) and somatic aspects of depression (such assleep, appetite, and libido).”

“…male hypogonadism is associated with marked deterioration of trabecular architecture and toa greater degree than bone densitometry of the spine and hip suggests.”

“…serum SHBG concentration is increased in middle-aged men with primary or secondary osteoporosis and is correlated with

bone remodeling markers, hip bone mineral density, and vertebral fracture risk.”

“Transdermal testosterone gel application for 6 months decreased bone resorption markers and increased osteoblastic activity markers for a short period, which resulted in a small but significant increase in BMD.”

Niveles bajos de andrógenosse relacionan con rigidez arterial

Niveles bajos de DHEAse relacionan con DM/DLP/CI

Niveles bajos de andrógenosse relacionan con ↑ riesgo CV

El tratamiento con Testosteronamejora los síntomas de angina de pecho y

reduce la isquemia miocárdica inducida por ejercicio.

Niveles bajos de testosterona están relacionadoscon mayor mortalidad

Regulación de eNOS, PDE5.

Metabolismo del tejido conjuntivo del pene.

↓cél musculares lisas ↓ elasticidad ↑colágeno III ↓ colágeno I

Traish A J Sex Med 2006; 3: 382-407

• El nivel de deseo sexual (IIEF-12) se asocia con elnivel de testosterona sérica.

• Los pacientes con testosterona sérica baja tienen menor nivel de deseo sexual.

• El tratamiento con testosterona aumenta el nivel de deseo sexual, las erecciones nocturnas y la frecuencia de las relaciones sexuales.

Ansong KS J Urol. 1999;162:719-21 Zitzmann M J Clin Endorinol Metab. 2006;91:4335-43 Wang C J Clin Endocrinol Metab. 2004;89:2085-98Seftel AD J Androl. 2004;25:963-72.

SÍNDROME DE DEFICIENCIA DE TESTOSTERONA, TESTOSTERONA Y PRÓSTATA.

Eduardo García Cruz

Servicio de Urología

Hospital Clínic de Barcelona

The great enemy of the truth is very often not the lie... But the myth, persistent, persuasive and unrealistic!

I. The effect of estrogens and androgen injection on serum phosphatases in metastatic carcinoma of the prostateCancer Res., 1941II. The effect of castration on advanced carcinoma of the prostate glandArch. Surg., 1941

Testosterone level is related to diagnose of adenocarcinoma of the prostate in hypogonadic patients but not in eugonadal patients.García-Cruz E, Huguet Pérez J, Ribal Caparrós MJ, Pérez Márquez M, Piqueras Bartolomé M, Alcaraz AHospital Clínic de BarcelonaIntroduction and Objectives:Prostate development is ruled by testosterone. On one hand, it is well known that testosterone deprivation induces PCa regression. On the other hand, previous data does not support the idea of high testosterone levels causing PCa to develop. Saturation Model might be the answer for this paradoxical relationship, in which relative small testosterone concentration is able to fully activate testosterone receptor. 

We prospectively analyzed 705 consecutive patients who underwent TRUS-guided prostate biopsies in the Department of Urology of the Hospital Clínic de Barcelona from September 2007 to June 2009. Indication for prostate biopsy was suspicious DRE or PSA elevation. Screening was carried out with 5+5 cores TRUS-guided prostate biopsy. As part of our clinical protocol, we determined hormonal pattern (Testosterone and SHBG) in this patients. Serum samples were obtained by puncture of fasting patients between 7:00-11:00 AM. Testosterone was determined with radioimmunoassay method. Patients who were receiving LH-releasing hormone analogues or testosterone replacement therapy were excluded from the analysis. Following ISA-ISSAM-EAU Guidelines recommendations, we considered T cutpoints 231 and 346 ng/dL as diagnosis of biochemical hypogonadism. 124 patients had a total testosterone below 346 ng/dL and were considered biochemically hypogonadal. We prospectively record age, BMI, toxic habits, number of previous biopsies, PSA, free-to-total PSA, dPSA, DRE, prostate volume and final pathology report.Results:Testosterone 443±167 ng/dL in non-PCa patients vs 439±171ng/dL in PCa patients, p=0,831; SHBG: 44±19 ng/dL in non-PCa patients vs 52±27 ng/dL in PCa patients, p=0,000). In relation to PCa diagnose, variables free PSA (p=0,008), dPSA (p=0,039), Prostate volume (p=0,016), DRE (p=0,033) and Number of previous biopsies (p=0,037) remained statistically significant after multivariate analysis.In low testosterone patients (TT<346 ng/dL), testosterone levels were related to PCa diagnose (272±55 in non PCa patients ng/dL vs 235±94 ng/dL in PCa patients, p=0,004). In low testosterone patients (TT<346 ng/dL), SHBG was in relationship to PCa (non-PCa 32±10 vs PCa 38±15, p=0,016). Variables DRE (p=0,003), Prostate Volume (p=0,037), Testosterone (p=0,006) and SHBG (p=0,014) remained statistically significant after multivariate analysis in low testosterone patients.Conclusions:Testosterone levels are not related to PCa diagnose, although PCa patients had higher SHBG levels. In low testosterone patients, low testosterone levels and high SHBG levels were related to PCa diagnose.

Testosterone (ng/dL): Non Adenocarcinoma 457,08±167,17 vs Adenocarcinoma 431,31±173,19, P=0,196; SHBG (nmol/L): Non adenocarcinoma 45,06±19,15 vs Adenocarcinoma 47,25±18,54, p=0,336

Adenocarcinoma

AdenocarcinomaNo adenocarcinoma

Te

sto

ste

ron

e (

ng

/dL

)

350

300

250

200

150

100

50

0

Testosterone levels are not related to PCa diagnose, although PCa patients had higher SHBG levels. In low testosterone patients, low testosterone levels and high SHBG levels were related to PCa diagnose.

Área bajo la curva

,542

,548

Variables resultadode contrastePSA/Testosterona

PSA

Área

La variable (o variables) de resultado de contraste:PSA tiene al menos un empate entre el grupo deestado real positivo y el grupo de estado realnegativo. Los estadísticos pueden estar sesgados .

PSA/Testosterona

No PCa 2,34±2,1

PCa 8,2±24,8

P=0,002

LOW TESTOSTERONE LEVELS ARE ASSOCIATED WITH POOR PROGNOSIS RISK FACTORS ON NEEDLE PROSTATE CANCER BIOPSIES.

M Pérez Márquez; E García-Cruz; M Piqueras Bartolomé; A Ciudin; J Huguet Pérez; MJ Ribal Caparrós; A Alcaraz Asensio. Urology Department. Hospital Clínic de Barcelona. Spain.

Methods: Between June 2007 and May 2009, we prospectively recorded 179 consecutive patients diagnosed of Prostate Cancer in our centre with TRUS prostate needle biopsies. Hormonal pattern was determined in our centre as part of our clinical protocol in patients diagnosed of prostate cancer. Variables age, BMI, PSA, free to total PSA, number of previous biopsies, DRE, Gleason score, bilaterality of tumour in both prostate lobes samples and percentage of tumour compared to total tissue sample were prospectively recorded. We subclassified patients using D’Amico criteria to predict risk of progression. Testosterone cutpoints (231/346 ng/dL) were used to define TDS following ISA-ISSAM-EAU Guidelines recommendations.

Conclusion: Patients with adenocarcinoma of the prostate and lower testosterone level are affected by more extensive disease and are at higher risk of progression. These findings reinforce the idea that testosterone deficiency is in relation with poor prognosis factors in patients with prostate cancer.

Background:

Low testosterone levels have been related to poor prognosis factors in prostate cancer. The aim of our study was to determine relationship between testosterone levels and prognosis factors in patients diagnosed of prostate cancer with TRUS needle biopsies.

res

Results: Age 68+/-9; PSA 58+/-464 (median 8.14); DRE T1 61%, T2 33%, T3 or more 6%; Gleason score 2-6 59%, Gleason 7 28%, Gleason 8-10 13%; First biopsy 78%, Second biopsy 11%, Third or further 11%; Prostate volume 43+/-23 cc,

Testosterone (ng/dl) 435+/-171; Testosterone>346ng/dL 73%, Testosterone 231-346 ng/dL 18.5% and Testosterone <231ng/dL 8.5%.

In univariate analysis, testosterone was related to risk of progression (Low risk 482±193, intermediate risk 452±163 and high risk 340±131 (p=0.012)), bilaterality of the tumour (unilateral 483±161 and bilateral 354±161 (p=0.000)) and percentage of the tumour in biopsy sample (B -0.988, β -0.254, p=0,004). Testosterone was not in relationship with DRE staging (T1 448±176, T2 451±105, T3 or more 335±202 (p=0.296)), PSA (PSA <10 462±168, PSA 10-20 425±167, PSA≥20 350±174 (p=0.09)) or Gleason score (Gleason 2-6 458±187, Gleason 7 445±151, Gleason 8-10 347±115 (p=0.066)).

<7 7 >7

Se debería determinar Testosterona a todos los pacientes con Adenocarcinoma de Próstata.

Es planteable determinar Testosterona a los pacientes en screening por elevación del PSA.

Es planteable considerar pacientes de mal pronóstico a pacientes con Adenocarcinoma de próstata y T<346 ng/dL. Esto podría tener implicaciones en el tratamiento.

5. Tratamiento.

Iniciar tratamiento tópico. Pasar a tratamiento parenteral.

Control trimestral (Hematocrito/perfil hepático/PSA-PSA libre/TR).

Objetivo: niveles de testosterona normales.

Objetivo: mejoría clínica.

“These data suggest that acute exercise enhances the local bioactive androgen metabolism in the skeletal muscle of both sexes.”

“…gastric bypass-induced weight lossimproves hormonal and EFs in morbidly obese mencompared with non-surgical weight loss.”

“Mean body weight decreased more in patients in the intervention group (−4.0 [1.1] kg) than in those in the control group (−1.2 [0.6] kg) . Compared with patients consuming the control diet, patients consuming the intervention diet had significantly reduced serum concentrations of hs-CRP.”

“Lifestyle changes are associated with improvement in sexual function in about one third of obese men with erectile dysfunction at baseline.”

1. Fisiología de la testosterona

2. TDS: definición, clínica y diagnóstico

3. Prevalencia y etiología

4. Fisiopatología

5. Tratamiento

edu_garcia_cruz@yahoo.com

SÍNDROME DE DEFICIENCIA DE TESTOSTERONA

Eduard García CruzUrologia

Hospital Clínic de Barcelona

Déficit de Testosterona

Eduard García CruzUrología y Salud del Hombre

Servicio de UrologíaBarnaclínic

Hospital Clínic de Barcelonaecruz@clinic.ub.es

@drgarciacruzwww.reisho.com

Conflict of interest: he recibido fondos para investigación de BAYER, Lilly, Pfizer, Auxilium y Janssen, he formado parte de comités asesores para Bayer, Lilly, Gebro, Almirall, Janssen, Italpharmaco y Menarini. Soy ponente para Lilly, Pierre Fabre y Bayer.