Voorkomen, Substitueren of accepteren? Dr.Ir. B.E.P.B ...Wu F C W et al. JCEM 2008;93:2737-2745...
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Penopauze Voorkomen, Substitueren of accepteren? Dr.Ir. B.E.P.B. Ballieux, LUMC PAOKC ’65+, jong en vitaal’ 28 juni 2012 Driebergen
Transcript of Voorkomen, Substitueren of accepteren? Dr.Ir. B.E.P.B ...Wu F C W et al. JCEM 2008;93:2737-2745...
PenopauzeVoorkomen, Substitueren of accepteren?
Dr.Ir. B.E.P.B. Ballieux, LUMC
PAOKC ’65+, jong en vitaal’28 juni 2012 Driebergen
Penopauze
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“Male climacteric”
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"viropause”
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“Andropauze”
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“Male senescence”
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"late onset hypogonadism"
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“Partial androgen deficiency in aging men" (PADAM)
Analogie met menopauze?
Andropauze = $ € £ ¥ ₯
Maar!
Overzicht
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Introductie
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Relatie testosteron afname met leeftijd en morbiditeit
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Testosteron substitutie• Effect
• Veiligheid
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Analysemethoden
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Conclusies
The European Male Aging Study (EMAS)
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3369 mannen tussen 2003 en 2005 geincludeerd
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8 landen in Europa
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Baseline data
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Follow up
Hypothesis EMAS•
“inter-individual and regional variability in symptomatic dysfunctions,
alterations in body composition and health outcomes in ageing men can be explained by different rates of decline in anabolic hormones, the most important of which being testosterone”
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Study was “expanded to encompass age-related changes across multiple physiological systems to better describe the ageing phenotype”
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Participants were “broadly representative of the local adult population in each centre”
Resultaten EMAS baseline
Relationship between age and hormones.
Wu F C W et al. JCEM 2008;93:2737-2745
©2008 by Endocrine Society
Presentator
Presentatienotities
Relationship between age and hormones. This shows the mean hormone values at 5-yr age bands with 95% CI (shaded area) in 3220 men. Mean hormone values with increasing age were interpolated to approximate the age trend. Total T and free T were significantly lower and LH and SHBG significantly higher in the older age groups. There was an apparent inflection point around 70 yr for LH.
Relationship between age, BMI, and hormones.
Wu F C W et al. JCEM 2008;93:2737-2745
©2008 by Endocrine Society
Presentator
Presentatienotities
Relationship between age, BMI, and hormones. The cohort was stratified according to BMI into three groups: nonobese (BMI < 25 kg/m2), overweight (BMI ≥ 25 to < 30 kg/m2), and obese (BMI ≥ 30 kg/m2). Mean (95% CI in shaded area and vertical lines) total and free T and SHBG were significantly lower in the overweight and obese at all ages, compared with nonobese. The total T and SHBG age trends in the three BMI categories were similar (indicating no interaction between BMI and age); the free T age trend in the obese group was less steep than in the other two groups (indicating an interaction between BMI and age). Mean LH was not significantly different among the three groups at the median age of 60 yr. LH was higher in the older than 70 yr nonobese, compared with the overweight and obese groups, due to a negative BMIage interaction. For details, see Results and Table 2.
Relationship between age, comorbidity, and hormones.
Wu F C W et al. JCEM 2008;93:2737-2745
©2008 by Endocrine Society
Presentator
Presentatienotities
Relationship between age, comorbidity, and hormones. The cohort was stratified in men with no comorbidity and those with one or more comorbid conditions. Mean (95% CI in shaded area and vertical lines) total T was significantly reduced in the comorbid group across all age bands. Free T, SHBG, and LH (at median age 60 yr) showed no difference between the comorbid groups. A steeper LH slope was seen in men older than 70 yr with comorbidity, compared with those without, indicating a positive interaction effect between age and comorbidity. For details, see Results and Table 2.
Massachusetts Male Aging Study
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A prospective
cohort study of health and endocrine functioning
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1709 randomly selected men at baseline visit (T1, 1987– 1989) in 3 age cohorts (40s, 50s and 60s)
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Two follow-up visits (T2, 1995–1997; T3, 2002–2004) with 1156 and 853 participants
T vs. age (natural log scale for all observations).
Travison T G et al. JCEM 2007;92:549-555
©2007 by Endocrine Society
Nmol/L
35
21
14
7
3.5
Presentator
Presentatienotities
TT vs. age (natural log scale for all observations). Linear trajectories for 20 randomly chosen subjects are plotted (thin lines), demonstrating the substantial intersubject variation in log T values and trends over time. A nonparametric, locally weighted regression smooth (thick line) depicts the linear decline in log T values with age over all observations, which is generally outstripped by within-subject longitudinal decline. To convert TT from nanograms per deciliter to nanomoles per liter, multiply by 0.0347.
The Relative Contributions of Aging, Health, and Lifestyle Factors to Serum Testosterone Decline in Men (Massachusetts Male Aging Study)
Selected health/lifestyle changes and crude T decline from T1 to
T21
Health/lifestyle factor N2
Mean decline (%)3
TT FT
Increased chronic illness
No illness T1 and T2 382 −4.0 −7.3
No illness T1, one or more illnesses T2 162 −6.3 −13.1
Increased use of medications
Fewer than six medications T1 and T2 889 −5.0 −9.6
Fewer than six medications T1, six or more T2 49 −9.9 −13.4
Smoking cessation
Smoker T1 and T2 112 1.6 −6.9
Smoker T1, nonsmoker T2 93 −7.6 −11.0
Loss of spouse
Married T1 and T2 680 −6.0 −12.0
Married T1, widowed T2 25 −16.9 −21.2
1 Proportionate TT and FT declines are sharper among subjects who are healthy at T1 and experience subsequent loss of health at T2 than among subjects who remain healthy. Similar patterns are evident with respect to incident chronic illness, increased use of medications, smoking cessation, and loss of spouse.
2 Summaries are restricted to subjects with T and health/lifestyle data at T2.
3 Proportionate decline is calculated with respect to baseline T levels.
Travison TG et al. JCEM 2007;92:549
Changes in health status can account for a substantial portion of longitudinal androgen decline.
Travison T G et al. JCEM 2007;92:549-555
©2007 by Endocrine Society
Presentator
Presentatienotities
Changes in health status can account for a substantial portion of longitudinal androgen decline. The estimated difference (12%) in T levels between subjects who are obese and those who are not is comparable to the decline (13%) observed over 10 yr of aging among subjects whose BMI remained stable, so that “jumping the tracks” (thick line) is associated with a substantial additional decline in T concentrations. The underlying linear decrease in T among subjects with incident obesity (dotted line) is therefore accelerated beyond that observed in subjects whose obesity status is unchanged.
EMAS: Definition Late onset Hypogonadism
LOH:
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3 sexual symptoms:• Libido ↓
• Morning erections ↓
• Erectyle dysfunction↑
Plus
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T < 11 nmol/L and free T < 220 pmol/L
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Moderate: T>8 and <11 nmol/L
free T <220 pmol/L
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Severe: T< 8 nmol/L and
free T < 220 pmol/L
Association between selected end points and LOH (A) and low T (B) (irrespective of symptoms, compared to no LOH).
Tajar A et al. JCEM 2012;97:1508-1516
©2012 by Endocrine Society
moderate (□) and severe (■) LOH T 8–11 nmol/liter (□) and T < 8 nmol/liter (■)
Results are adjusted for age, BMI, smoking status, and comorbidity.
Presentator
Presentatienotities
Association between selected end points and LOH (A) and low T (B) (irrespective of symptoms). Values are standardized β-coefficients (per sd) and 95% CI for the difference in mean values of the end point between moderate (□) and severe (■) LOH (A) and T 8–11 nmol/liter (□) and T < 8 nmol/liter (■) (B) compared with the eugonadal group. Results are adjusted for age, BMI, smoking status, and comorbidity.
Voorlopige conclusies
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leeftijdsafhankelijke afname van T, onafhankelijk van bij komende morbiditeiten, BMI en metabool syndroom
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BMI, metabool syndroom, comorbiditeiten geven een extra daling van T en of vrij testosteron
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Hypogonadisme met bijkomende sexuele problemen met name gerelateerd aan insuline resistentie.
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Mogelijk effect van vrije radicalen bij inflammatie op NO gemedieerde erectiele functie.
Metabool syndroom, insulineresistentie en testosteron
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Overgewicht en insulineresistentie leiden tot verlaagd SHBG en daardoor verlaging T (niet vrij T) t.o.v. slanke leeftijdsgenoten.
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Ernstig overgewicht ook vrij T↓
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Insulineresistentie en E2 feedback remt LH
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Ziekte en comorbiditeit op late leeftijd voegen nog een extra primair gonadaal falen toe (extra stijging van LH)
LH after caloric restriction
Roelfsema F et al. Metabolism 2011;60:1227
Tot zo ver alles duidelijk…….
Testosterone in aging males of good/excellent health
The Healthy Man Study. Sartorius G et al Clin Endocrinology 2012, in press
The Healthy Man Study. Sartorius G et al Clin Endocrinology 2012, in press
Testosterone in aging males of good/excellent health
The Healthy Man Study. Sartorius G et al Clin Endocrinology 2012, in press
Testosterone in aging males of good/excellent health
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Achteruitgang van testosteron tot in de 8e
decade vooral het
gevolg van ziekte en overgewicht.
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Pas in de 9e
decade significante primaire gonadale
achteruitgang met verlaging vrij testosteron
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Verdere analyse:• Vasten verhoogt alle steroidhormonen
• BMI : T afname van 0,5 nmol/L per BMI unit (kg/m2) E2 toename 2 pmol/L per BMI unit (kg/m2)
• Stoppen met roken verlaagt T
Kip en het ei?
T
Testosteron substitutie?
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Toename in het aantal recepten voor testosteron van 692.000 in 2000 naar 2.660.000 in 2008
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Beoogde doel:
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Erectiele dysfunctie, libido, sexuele tevredenheid
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Spierkracht, spiermassa
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BMI, body fat, metabool syndroom
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Gezondheid ouderen (Frailty)
Sexueel
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Boloña ER et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007 Jan;82(1):20-8.
• Minimaal effect op erectiele functie
• Significant effect op libido
• Geen effect op sexuele tevredenheid.
Testosteron en metabool syndroom
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Corona G et al. J Sex Med 2010 5 studies, 306 deelnemers, gemiddelde studieduur 58 weken
(verschillende: doseringen, definities hypogonadisme)
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Kleine maar significante effecten op:• Nuchter glucose
• HOMA index
• Buikomvang
• Triglyceriden
• HDL cholesterol
Testosterone and Metabolic Syndrome: A Meta-Analysis Study
Corona et al. The Journal of Sexual Medicine 2010; 8: 272-283
Presentator
Presentatienotities
Weighted differences (with 95% confidence interval [CI]) of mean fasting glycemia, homeostatic model assessment index, triglycerides, high‐density lipoprotein cholesterol and waist circumference at end point across randomized controlled trials. The size of the circles reflects the sample dimension. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party.
Testosteron substitutie en type 2 DM
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Corona G et al. Int J Andrology 2010 4 studies, 228 deelnemers, studieduur 12 –
52 weken
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Kleine maar significante effecten op:• HbA1c
• Nuchter glucose
• Vetmassa
• Triglyceriden
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Geen significant effect op• Totaal of HDL cholesterol, bloeddruk en BMI
Type 2 diabetes mellitus and testosterone: a meta-analysis study
Corona G et al. International Journal of Andrology 2010; 34: 528-540
Presentator
Presentatienotities
Weighted differences (with 95% confidence interval) of mean HbA1c, fasting glycaemia, triglycerides and fat mass at endpoint across randomized controlled trials. Duration of the studies: Boyanov et al. (2003), 12 weeks; Kapoor et al. (2006), 12 weeks; Heufelder et al. (2009), 52 weeks; Jones et al. (2010), 52 weeks. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party.
Frailty
O'Connell MD et al. Low testosterone in ageing men: a modifiable risk factor for frailty? Trends Endocrinol Metab. 2011 Dec;22(12):491-8.
T treatment and frailty
O'Connell MD, et al. Trends Endocrinol Metab. 2011 Dec;22(12):491-8.
Relatie Testosteron en frailty
O'Connell MD, et al. Trends Endocrinol Metab. 2011 Dec;22(12):491-8.
Effect T substitutie op frailty
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Alleen effect op de meest zwakke onderzoekspopulaties
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Effect gerelateerd aan toename spiermassa
O'Connell MD, et al. Trends Endocrinol Metab. 2011 Dec;22(12):491-8.
Tekortkomingen
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Verschillende doseringen
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Verschillende definities van:• Hypogonadisme
• Metabool syndroom
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Verschillende tijdsduur van interventie
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Etc.
Effect T suppletie in hypogonadale mannen in een 12 maanden prospectieve RCT
Is T substitutie veilig?
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Cardiovasculair
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Lipidenprofiel
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Prostaat
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Diabetes
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Hartritmestoornissen
Results of the random effects meta-analyses of testosterone on patient-important outcomes.
Fernández-Balsells M M et al. JCEM 2010;95:2560-2575
©2010 by Endocrine Society
Presentator
Presentatienotities
Results of the random effects meta-analyses of testosterone on patient-important outcomes.
IA or MS?
Huhtaniemi IT et al. Eur J Endocrinology 2012;166:983
Conclusies
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Testosteron afname bij toenemende leeftijd is geen vaststaand gegeven. (geen Andropauze)
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Deel maar niet alle factoren van testosteron afname bekend
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Obesitas en metabool syndroom hebben evenveel effect op T afname als 10 jaar veroudering (onbekende overige effecten)
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Vrij testosteron berekening nodig om in het grensgebied een uitspraak te kunnen doen
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Klinische sexuele symptomen passen bij ernstige T deficientie
