3. Testosterone therapy is prescribed for
millions of men each year, and the number
is increasing rapidly.
Prescription sales of testosterone increased
by 500% in the United States between 1993
and 2000.
Liverman CT, Blazer DG. Testoster-
one and aging: clinical research direc-
tions. Washington, DC: National Acade-
my of Sciences, 2004.
4. Most testosterone prescriptions are written
to treat non-specific symptoms, such as
fatigue or sexual dysfunction, when
accompanied by testosterone levels below
the laboratory reference range.
5. More than 80% of circulating
estradiol in men is derived from the
aromatization of testosterone.
Thus, as serum testosterone levels
decline, there is a concomitant
decline in serum estradiol levels.
6. The potential role of estrogen deficiency
in the pathogenesis of other consequences
of hypogonadism, such as alterations in
body composition or sexual function, is
largely unknown
ESTROGENIO???????
7. 2 COORTES COM HOMENS 20-50 ANOS COM TT NORMAL
TODOS RECEBERAM ZOLADEX 3,6 – SEMANAS 0,4,8 E 12
RANDOMIZACAO
1- PLACEBO, E
DOSES VARIADAS
DE GEL POR 16
SEMANAS
2- PLACEBO, E
DOSES
VARIADAS DE
GELPOR 16
SEMANAS
+ ARIMIDEX
8. Participants were seen every 4 weeks.
At each visit, fasting blood samples were
obtained to measure gonadal steroid
levels, and questionnaires were
administered to assess physical function,
health status, vitality, and sexual
function.
9. At baseline and week 16, body fat and lean mass were
assessed by means of dual-energy x-ray
absorptiometry (DXA); subcutaneous- and
intraabdominal-fat areas and thigh-muscle area were
measured by means of computed tomography (CT);
and lower-extremity strength was de- termined by
means of a leg press.
Data on bone homeostasis (bone-turnover markers and
bone mineral density), risk factors for cardiovascular
disease (blood pressure, lipids, and insulin sensi-
tivity), and levels of leptin and prostate-specific
antigen were also collected but are not included in the
present report.
10. In cohort 1, the percentage of body fat increased
significantly in men who received 0 g, 1.25 g, or
2.5 g of testosterone daily, as compared with men
who received 5 g daily, and it decreased
significantly in men who received 10 g of
testosterone daily, as compared with each of the
other groups
Lean mass decreased significantly in men who received
placebo or 1.25 g of testosterone daily, as compared
with men who received 2.5 g, 5 g, or 10 g of testosterone
daily
11. Thigh-muscle area decreased significantly in men
who received placebo or 1.25 g of testosterone
daily, as compared with men who received 5 g of
testosterone daily, and it increased significantly
in men who received 10 g of testosterone daily,
as compared with all the other groups
Leg-press strength decreased significantly
in men who received placebo, as compared
with men receiving 2.5 g, 5 g, or 10 g of
testosterone daily
12. Cohort 2 = com arimidex
In cohort 2, the percentage of body fat
increased in all groups when the
aromatization of testosterone to estradiol
was inhibited.
A finding that suggests a predominantly
estrogenic effect
13. Cohort 2 = com arimidex
Total body lean mass decreased significantly
in men who received placebo, as compared
with those who received 1.25 g, 2.5 g, or 10 g
of testosterone daily
A finding that implies an independent effect of
testosterone
14. Effects of Testosterone with and
without Aromatase Inhibition on
Sexual Function
In cohort 1, sexual desire decreased progressively
with declining testosterone doses, from 10 g to 0 g of
testosterone daily, and all dose groups differed
significantly from one another except for the 2.5g
and 5g dose groups
Erectile function worsened significantly in men
who received placebo, as compared with men who
received testosterone
15. In cohort 2, sexual desire declined significantly in men
who received placebo, as compared with men in the
three highest dose groups, and declined more in men
who received 1.25 g of testosterone daily than in men
in the two highest dose groups
Erectile function decreased more in men
who received placebo than in men who
received testosterone
16. Comparação with and without
Aromatase Inhibition on Sexual
Function
In the groups that received testosterone, inhibition of estrogen
synthesis (cohort 2), as compared with intact estrogen
synthesis (cohort 1), was associated with significant increases
in the percentage of body fat (P<0.001), subcutaneousfat area
(P<0.001), and intraabdominalfat area (P=0.002) and with
significant decreases in sexual desire (P<0.001)
These findings provide additional evidence of an
independent effect of estradiol on these measures
17.
18. We found that lean mass, muscle size, and strength
are regulated by androgens; fat accumulation is
primarily a consequence of estrogen deficiency;
and sexual function is regulated by both
androgens and estrogens.
Delineation of the degrees of hypogonadism at
which undesirable consequences develop and of
the relative roles of androgens and estrogens in
each outcome should facilitate the development of
more rational approaches to the diagnosis and
treatment of hypogonadism in men.
22. Integração da Sociedade Americana
1. Guidelines da Sociedade Int. Andrologia (ISA)
2. Sociedade Européia de Urologia (EAU)
3. ISSAM
1. Sociedade Americana de Andrologia (ASA)
2. EAA ( Academia e. Andrologia)
Consenso publicado Euro J Urology e Euro J. Endrocrinol – Tampa 2008
23. IMPORTANCIA NO BRASIL
1. Crescimento exponencial de homens > 60 anos – como PEA
2. Vida sexual ativa prolongada > 60/70 anos
3. Crescimento do país = > poder aquisitivo
4. Maior exigência de performance
Sub Avaliados
24. Subavaliação e subtratamento
Problemas encarados como normais
Geralmente não se conhece os efeitos da queda
gradual da testosterona
Outras especialidades – receio de reposicão
Mitos (falta de conhecimento)
Papel da mulher fundamental
26. De 32 sintomas possivelmente associados à queda dos níveis de
testosterona, nove confirmaram guardar relação direta com ela
Ligados à sexualidade (frequência diminuída de ereções matinais
espontâneas, de pensamentos eróticos e disfunção erétil),
Físicos (dificuldade de praticar exercícios como correr ou levantar
objetos pesados, incapacidade de andar mais de 1 km e de
ajoelhar e levantar sem ajuda)
“psicológicos” (falta de energia, fadiga e tristeza).
27. Diagnóstico de DAEM
• Testosterona Total ( 7 - 11h da manhã)
• > 350/380 – sem indicação de reposição, qual a
crítica a este critério?
• < 230 – reposição em todos
• 230 – 380 = avaliar caso a caso e pede SHBG =
Testosterona livre calculada
• Cuidado com obesos – importância de T livre
biodisponivel (SHBG reduzido)
• T livre < 65 = reposição
29. Exames pré reposição
Hemograma completo e coagulograma
PSA total e livre (TR)
Densitometria óssea ( > 65 anos )
Testosterona total, T livre, glicemia, TSH, T4
livre, creatinina, SHBG, prolactina, FSH e
albumina. Colesterol T e F
30. Diagnóstico de DAEM
• T livre salivar = substituto
independe dos niveis de albumina e
SHBG
( laboratório Jablonka- Itaim)
Testosterona livre tem atividade
biológica mas ligada a SHBG não
Homens com hipogonadismo
geralmente tem SHBG elevado ( disf
hepática e hipertireoidismo tb)
31. METAS NA REPOSICAO
HORMONAL
Massa Muscular e osséa comprovados por
densitometria (nivel 1a)
e medidas antropométricas
Efeitos sobre melhora DM e resistência a insulina
ainda incertos
Libido comprovado (nivel 1b)
Disposição fisica e melhora do humor
32. Os implantes extruídos eram limpos, secados e pesados para
determinar a massa de testosterona liberada em comparação com
a função linear do tempo acima de 120 dias.
33. Farmacocinética
Para cada tubo contendo 200 mg de
testosterona, a taxa estimada de absorção
foi de 1,3 mg/dia, baseada no peso
remanescente de 59 implantes extruídos
que exibiram taxa linear de absorção
durante mais de cem dias após
implantação
(Handelsman et al., 1990)
34. • Effects on sexual interest = 3 weeks plateauing at 6 weeks.
• Changes in erections/ejaculations = require up to 6 months.
• Effects on depressive mood = detectable after 3–6 weeks with a
maximum 18–30 weeks.
• Effects on erythropoiesis = evident at 3 months, peaking at 9–12 months.
• Effects on lipids = after 4 weeks, maximal after 6–12 months.
• Insulin sensitivity may improve within few days, but effects on glycemic
control become evident only after 3–12 months.
• Changes in fat mass, lean body mass, and muscle strength = within 12–
16 weeks,
stabilize at 6–12 months, but can marginally continue over years.
• Effects on bone are detectable already after 6 months while continuing
at least for 3y
POLIMORFISMO DO
RECPETOR ANDROGENICO
35.
36. Papel testosterona na ereção
Essencial para a manutenção do metabolismo dos corpos
cavernosos do pênis e da sua integridade estrutural e
funcional, que regulam o mecanismo de veno-oclusão da
função erétil.
Diminuição das trabéculas das células lisas dos corpos cavernosos, um queda da
síntese do NO no endotélio vascular e produz alterações estruturais dos nervos dorsal
e cavernosos do pênis
Acúmulo de células gordurosas e tecido conjuntivo nos corpos cavernosos, diminuindo o
numero células responsáveis pelo relaxamento do pênis
A reposição hormonal pode desempenhar papel
fundamental na recuperação da fisiologia da ereção
37. Homens com baixos índices de testosterona e que
não respondiam bem aos inibidores da PDE-5
passaram a responder melhor após a reposição
hormonal.
Antes de iniciar tratamento para DE = guideline
mandatório dosagem de T total
38. Acompanhamento
PSA e TR semestrais
Densitometria anual
Hematócrito semestral
(eritrocitose – homens acima de 70 com injetáveis)
Elevação de PSA = biópsia PR ( e implante? )
39. Contra Indicações
• Apnéia do sono não tratada
• Insuficiência Cardiaca CF II – médios esforços
• Ht > 52%
• Hiperplasia prostática benigna ( relativa –
depende dos sintomas HPB )
• História de CA próstata já tratado – !!!!!!! *****
• Levar em conta HX familiar de Ca próstata
40. Subcutaneous T pellet implants have been available in the United
States since 1972 and afford several advantages over other T
formulations
100% patient compliance
Avoidance of the peaks and troughs found with injectable treatments
Lower risk of drug transfer from patient to others
Maintenance of a stably elevated serum T level.
While T pellets are used to treat androgen deficiency, limited data
exist regarding their pharmacokinetics and side effect profiles
(Cavender and Fairall, 2009). Furthermore, the incidence of
erythrocytosis and effects on lipid profiles is relatively unknown for T
pellets.
41. Trabalhos Importantes
J Urol. 2005 Feb;173(2):533-6.Testosterone replacement therapy after
primary treatment for prostate cancer
A cohort of hypogonadal patients treated with radical retropubic
prostatectomy (RRP) for organ confined prostate cancer to determine if
testosterone replacement therapy (TRT) could be efficacious and
administered safely without causing recurrent prostate tumor
19 MESES DE SEGUIMENTO – 10 PACIENTES POS PRR
TT 197 – 591 ( P≤0,0002)
MELHORA DOS FOGACHOS E ENERGIA
NENHUMA RECORRENCIA
APOS 19 MESES TODOS COM PSA < 0,1
42. Testosterone Replacement for Hypogonadism After
Treatment of Early Prostate Cancer With
Brachytherapy
• Pacientes tratados com braquiterapia entre 1996 e 2004 +
hipogonadismo sintomático – 31 homens
• TRT iniciando em média 2 anos após
• Duração de tratamento em média de 4,5 anos
• 200 mg ciprionato de testosterona 21/12d
43.
44. In highly select patients
after RRP TRT can be
administered carefully and
with benefit to hypogonadal
patients with prostate
cancer.
46. Principio da uro-oncologia > 70 anos
Hipótese androgênica para o câncer de
próstata
Surge com 2 prêmios Nobel
- Charles Huggins e Clarence Hodges (1941)
- Cancer Research 1941 – castração =
regressão do câncer metastático e
administração de T = elevação da FA
47. Desenvolvimento da teoria – até 80
• CAp é androgênio dependente
• Niveis elevados de T contribuem
para desenvolvimento de CAp
• Niveis reduzidos de T diminuem
riscos de CAp
• T = alimento para o incêndio
48. E o que parecia estar errado?
• Biópsias em homens com níveis baixos de
T antes da reposição hormonal
• 15% de câncer de próstata em homens
com PSA normal e toque retal normal.
(JAMA 2004 e Urology de 2006)
• 1 em cada 7 homens com níveis reduzidos
de T tinham CAp oculto –
Efeito protetor dos níveis baixos de T ?
49. E como derrubar o resultado de 1941 da
progressão do cancer em homens com
CA EIV e que receberam T?
Análise do trabalho – apenas 18
dias, 2 homens e com FA (não se
usa mais) – pouco tempo, não
suficiente para saturar.
51. Braço Placebo
Estudo REDUCE – Dutasterida
J Urol 2004
• Relação entre T/DHT e biópsias no braço
placebo – que não recebeu Avodart
• 8.122 homens – 4.073 foram placebo
• Destes 3.255 – BIOPSIAS
• Resultados destas BX versus T/DHT