Hormone Concentrations in Older Men Reporting Good Health
Hormone Concentrations in Older Men Reporting Good Health
Objective To determine serum concentrations, intra-individual variability and impact of age-related co-morbidities on serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) in older men.
Design Observational, repeated measures study.
Participants Men (n = 325) with 40 years and older self-reporting very good or excellent health.
Measurements Standardized history, physical examination and collection of nine blood samples at fixed time intervals were measured over 3 months (three at 20 min intervals on days 1 (fasting) and 2 (non-fasting), one at days 7, 30 and 90). Serum T, DHT, E2 and E1 (n = 2900, > 99% of scheduled samples) measured by liquid chromatography-tandem mass spectrometry (LC-MS) were analysed by linear mixed model analysis with fasting, age and obesity as covariables.
Results Mean serum T did not vary with age (P = 0·76) but obesity (−0·35 nM per body mass index (BMI) unit, P < 0·0001) and ex-smoker status (−1·6 nM, P < 0·001) had significant effects. Serum DHT was increased with age (+0·011 nM per year, P = 0·001) but decreased with obesity (−0·05 nM per BMI unit, P < 0·0001). Serum E2 did not vary with age (P = 0·31) or obesity (P = 0·12). Overnight fasting increased (by 9–16%, all P < 0·001) and reduced variability in morning serum T, DHT, E2 and E1. Non-fasting serum T and DHT were stable over time (day, week, month or 3 months; P > 0·28).
Conclusions Serum T, DHT and E2 displayed no decrease associated with age among men over 40 years of age who self-report very good or excellent health although obesity and ex-smoking status were associated with decreased serum androgens (T and DHT) but not E2. These findings support the interpretation that the age-related decline in blood T accompanying non-specific symptoms in older men may be due to accumulating age-related co-morbidities rather than a symptomatic androgen deficiency state.
The decline in blood T during male ageing is well known from numerous observational studies since the advent of T immunoassay in the early 1970s. Such studies are typically cross-sectional and obtain only a single blood sample for T measurement. More recent longitudinal studies involving serial blood sampling have appeared although still relying on single blood samples per timepoint which frequently are inconsistent. Although causality cannot be ascribed from observational studies, the coincidence of declining blood T concentrations with non-specific symptoms that are consistent with, but not diagnostic of, androgen deficiency (AD) has led to the 'andropause hypothesis', which postulates that these symptoms may be due to age-related AD. Using the analogy of unequivocal hormone deficiency states, such as pathologically based AD in young men and menopause, this proposes that symptomatic age-related AD may contribute a reversible component to deterioration in somatic and reproductive health of older men. Definitive testing of this hypothesis requires a placebo-controlled, randomized clinical trial that remains a prospect for the future. The alternative view is that the decline in blood T levels in older men is a consequence of the accumulation of co-morbidities of ageing which can depress blood T levels unrelated to the coincidental non-specific symptoms of chronic disease that resemble those of AD. This alternative hypothesis, whereby blood T is effectively a non-specific barometer of (ill)-health, cannot be proved directly but would be a plausible interpretation if the andropause hypothesis is refuted. In the interim, while the andropause hypothesis remains untested, consensus clinical guidelines and analysis of large scale observational studies tentatively define age-related AD ('andropause', 'late-onset hypogonadism') providing tacit support for unproven T treatment of older men according to criteria that combine non-specific symptoms and blood T thresholds into a putative diagnosis of age-related AD.
Yet the relationship of non-specific symptoms of AD to blood T levels remains poorly defined. Unequivocal AD, such as after bilateral orchidectomy or severe defects in Leydig cell T secretion in otherwise healthy young men, produces varied but characteristic symptoms accompanying low blood T levels. With the exception of flushing, which is rare apart from acute androgen deprivation, the non-specific symptoms of chronic AD also feature in other hormonal deficiency states as well as chronic diseases. This creates intractable confusion in evaluating individual older men where the background accumulation of age-related co-morbidities provides multiple potential etiologies for the non-specific symptoms. In younger men with organic, pathologically based disorders causing AD, the symptoms of AD display highly reproducible blood T thresholds within each person, although the leading symptoms vary widely in type and threshold between people. This distinctive individuality of thresholds means that when symptoms are grouped together, the apparent thresholds of blood T are attenuated while among populations of older men without pathologically based AD, such blood T thresholds for the same non-specific symptoms display minimal or no cutpoints.
This study aimed to measure age-specific serum concentrations of the major sex steroids (T, DHT and E2) among healthy older men as well as estimating the within-individual variability and the impact of common age-related co-morbidities (obesity, smoking). Based on the focus to define the nature of non-specific symptoms associated with AD, we therefore planned to recruit men who reported being in very good or excellent health, an elite cohort (rather than a community representative study population) from which to deduce the relationships between blood sex steroid levels and age and its related co-morbidities free from influence of non-specific symptoms of AD.
Abstract and Introduction
Abstract
Objective To determine serum concentrations, intra-individual variability and impact of age-related co-morbidities on serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) in older men.
Design Observational, repeated measures study.
Participants Men (n = 325) with 40 years and older self-reporting very good or excellent health.
Measurements Standardized history, physical examination and collection of nine blood samples at fixed time intervals were measured over 3 months (three at 20 min intervals on days 1 (fasting) and 2 (non-fasting), one at days 7, 30 and 90). Serum T, DHT, E2 and E1 (n = 2900, > 99% of scheduled samples) measured by liquid chromatography-tandem mass spectrometry (LC-MS) were analysed by linear mixed model analysis with fasting, age and obesity as covariables.
Results Mean serum T did not vary with age (P = 0·76) but obesity (−0·35 nM per body mass index (BMI) unit, P < 0·0001) and ex-smoker status (−1·6 nM, P < 0·001) had significant effects. Serum DHT was increased with age (+0·011 nM per year, P = 0·001) but decreased with obesity (−0·05 nM per BMI unit, P < 0·0001). Serum E2 did not vary with age (P = 0·31) or obesity (P = 0·12). Overnight fasting increased (by 9–16%, all P < 0·001) and reduced variability in morning serum T, DHT, E2 and E1. Non-fasting serum T and DHT were stable over time (day, week, month or 3 months; P > 0·28).
Conclusions Serum T, DHT and E2 displayed no decrease associated with age among men over 40 years of age who self-report very good or excellent health although obesity and ex-smoking status were associated with decreased serum androgens (T and DHT) but not E2. These findings support the interpretation that the age-related decline in blood T accompanying non-specific symptoms in older men may be due to accumulating age-related co-morbidities rather than a symptomatic androgen deficiency state.
Introduction
The decline in blood T during male ageing is well known from numerous observational studies since the advent of T immunoassay in the early 1970s. Such studies are typically cross-sectional and obtain only a single blood sample for T measurement. More recent longitudinal studies involving serial blood sampling have appeared although still relying on single blood samples per timepoint which frequently are inconsistent. Although causality cannot be ascribed from observational studies, the coincidence of declining blood T concentrations with non-specific symptoms that are consistent with, but not diagnostic of, androgen deficiency (AD) has led to the 'andropause hypothesis', which postulates that these symptoms may be due to age-related AD. Using the analogy of unequivocal hormone deficiency states, such as pathologically based AD in young men and menopause, this proposes that symptomatic age-related AD may contribute a reversible component to deterioration in somatic and reproductive health of older men. Definitive testing of this hypothesis requires a placebo-controlled, randomized clinical trial that remains a prospect for the future. The alternative view is that the decline in blood T levels in older men is a consequence of the accumulation of co-morbidities of ageing which can depress blood T levels unrelated to the coincidental non-specific symptoms of chronic disease that resemble those of AD. This alternative hypothesis, whereby blood T is effectively a non-specific barometer of (ill)-health, cannot be proved directly but would be a plausible interpretation if the andropause hypothesis is refuted. In the interim, while the andropause hypothesis remains untested, consensus clinical guidelines and analysis of large scale observational studies tentatively define age-related AD ('andropause', 'late-onset hypogonadism') providing tacit support for unproven T treatment of older men according to criteria that combine non-specific symptoms and blood T thresholds into a putative diagnosis of age-related AD.
Yet the relationship of non-specific symptoms of AD to blood T levels remains poorly defined. Unequivocal AD, such as after bilateral orchidectomy or severe defects in Leydig cell T secretion in otherwise healthy young men, produces varied but characteristic symptoms accompanying low blood T levels. With the exception of flushing, which is rare apart from acute androgen deprivation, the non-specific symptoms of chronic AD also feature in other hormonal deficiency states as well as chronic diseases. This creates intractable confusion in evaluating individual older men where the background accumulation of age-related co-morbidities provides multiple potential etiologies for the non-specific symptoms. In younger men with organic, pathologically based disorders causing AD, the symptoms of AD display highly reproducible blood T thresholds within each person, although the leading symptoms vary widely in type and threshold between people. This distinctive individuality of thresholds means that when symptoms are grouped together, the apparent thresholds of blood T are attenuated while among populations of older men without pathologically based AD, such blood T thresholds for the same non-specific symptoms display minimal or no cutpoints.
This study aimed to measure age-specific serum concentrations of the major sex steroids (T, DHT and E2) among healthy older men as well as estimating the within-individual variability and the impact of common age-related co-morbidities (obesity, smoking). Based on the focus to define the nature of non-specific symptoms associated with AD, we therefore planned to recruit men who reported being in very good or excellent health, an elite cohort (rather than a community representative study population) from which to deduce the relationships between blood sex steroid levels and age and its related co-morbidities free from influence of non-specific symptoms of AD.
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