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Try out PMC Labs and tell us what you think. Learn More. Several large cohort studies have disclosed the trajectories of sex steroids changes overtime in men and their clinical ificance. In men the slow, physiological decline of serum testosterone T with advancing age overlaps with the clinical condition of overt, pathological hypogonadism. In addition, the increasing of comorbidities, together with the high prevalence of chronic diseases, all further contribute to the decrease of serum T concentrations in the aging male. For all these reasons both the diagnosis of late-onset hypogonadism LOH in men and the decision about starting or not T replacement treatment remain challenging.
At present, the biochemical finding of T deficiency alone is not sufficient for diagnosing hypogonadism in older men. Coupling hypogonadal symptoms with documented low serum T represents the best strategy to refine the diagnosis of hypogonadism in older men and to avoid unnecessary treatments. Aging is associated with changes in the physiological functioning of the endocrine system. Vice versain aging males, the reproductive function progressively declines in parallel with the decrease of testicular function year by year 1 Accordingly, gonadotropins slightly increase in men while definitely soar at the time of menopause in women.
As far as sex hormones are concerned, it should be remarked that their production is different in men and women during adulthood: Older women sex Norman nm testosterone T is 10 folds higher in men than in women, while serum estradiol E 2 declines after the fifties in both sexes; thus sex hormones changes during aging differ by gender Fig.
Gender differences in aging related decline of sex hormones are outlined in Figure 1. This rate of decline in serum T corresponds approximately to a reduction of 3. The total amount of circulating serum T corresponds to the total serum T usually assayed into the clinic, which is the sum of both free T and T bound to serum proteins. A minimal part of circulating T bounds albumin and the strength of this binding is weak.
Vice versa T bound to SHBG is not promptly available for binding the androgen receptor due to the high strength of the binding; this represents the amount of circulating T which is not bioavailable. Several methods are available to measure the different fractions of circulating T.
Total serum T is the fraction most commonly measured in clinical practice and is usually assayed with Immunoassays IAs in clinical laboratories.
In general, for clinical purposes it is important to validate the assay and to perform continuous quality control, independently from the methodology used. The measurement of free serum T might be performed by means of equilibrium dialysis or ultrafiltration methods, which are, however, not manageable in clinical practice or, alternatively, by the use of direct free T assays, which are unreliable and strongly inaccurate.
Techniques for the measurement of bioavailable serum T are based on precipipation and separation of SHBG-bound T. For this reason, these methods are not simple and are not routinely employed in clinical laboratories. In addition, it is not clear the advantage of measuring bioavailable T rather than free T By taking into all the issues mentioned before, it becomes clear that the comparison of the coming from different studies suffers from bias due to methodological differences when measuring serum T and its decline during aging.
As serum T varies during the day 34 and seasonally, 25,35,36 it should be assayed in the morning and low values need to be confirmed twice in 2 different serum samples, the second one being obtained at least after 2 to 4 weeks after first T determination. Several risk factors have been associated with serum T decline. Longitudinal studies have shown that serum E 2 declines in parallel with serum T in men. Apart from the role of E 2 on bone, other several physiological functions have been attributed mainly to E 2.
Among them, the inhibitory effect of T on the hypothalamus and the pituitary seems to be due to a greater extent to its conversion into estrogens. At present less is known about the E 2 interindividual differences in serum among men with hypogonadism. However, it is possible to hypothesize that hypogonadal men with a higher aromatase activity might be protected from the decrease of E 2 when their serum T declines.
The measurement of serum E 2however, is not useful in clinical practice since the accuracy of IAs commonly used in the clinical laboratories is poor for the low values typical of the male range. One of the first studies investigating serum T in aging men by a longitudinal de was the New Mexico Process Study 52 that followed preliminary data ly obtained by cross-sectional studies.
The main characteristics of these studies are all summarized in Table 2. All these studies differ each other for several aspects, including the main aim of the study that not always is specifically addressed to the study of sex hormones decline during agingthe involvement of subjects of both genders, the duration of the study, and the of participants Table 2.
As expected, also the methodological approach differ among studies both in terms of methods used for the assessment of circulating sex steroids, the type of sex steroid assayed estradiol is not available from all the studiesthe study de, and the clinical investigations included in the study protocol, the latter varying widely among studies according to their primary and secondary endpoints Table 3Table 4.
Even though the comparison among all these studies goes beyond the aim of this review, we will try to report in a critical fashion Older women sex Norman nm aspects that are more relevant for the comprehension of the relationship between sex hormones and aging in Older women sex Norman nm. Main outcomes from large cohort studies investigating sex steroid changes occurring in aging. Among studies that have specifically investigated the decline of sex steroids, particularly T, in middle-aged to older men, the MMAS is one of the pioneering study, the investigation of sex hormones changes in aging being the main study endpoint Table 2.
The main aim of the study, however, was to evaluate the Older women sex Norman nm between sex hormones levels and osteoporosis rather than overtime changes during aging Table 2. The Rancho Bernardo Older women sex Norman nm started as a survey of heart disease risk factors in adults who were older than 30 y and lived in the southern California community of Rancho Bernardo, that has progressively accumulated a lot of data not only on CV system from this cohort across the last 40 years 59,65 Table 2.
For the majority of men, measurements of total T, E 2 and SHBG serum levels were available, even though the main aim of the study was not strictly related to hormonal changes overtime Table 2. The CHAMP study was originally deed in order to investigate the health status in men older than 70 y living in a defined geographical region near the Concord Hospital in Sydney. Almost all the studies found a decline of total serum T with advancing age Table 3Table 4. In the HIMS study, serum free T ificantly decreased with increasing age, while total serum T levels seemed to remain stable; this is probably due to the important increase of SHBG in older age, which could justify the persistence of stable total T levels 84 Table 3.
In line with other studies, also the RBS showed a decline of both total and bioavailable serum T levels with aging 80 Table 3. In particular, bioavailable serum T levels decreased more Even though the MrOS did not provide data on the trajectories of sex steroids overtime, it indirectly has confirmed that both serum T and E 2 decline with advancing age 86,87 Table 3.
By dividing participants according to quartiles of SHBG and sex steroids, in fact, their age was higher in the higher quartiles of serum SHBG 88 and in the lower quartiles of both serum E 2 86 and free T Vice versa no data on the decline of sex steroids were available in the InChianti study even though measurements of total T, E 2 and SHBG serum levels were available for the majority of men 67,70,85 in this study hormonal data were mainly used for investigating the association between circulating sex steroids and several conditions that are common in aging 69,68,67,70,66 Table 3.
The prevalence of biochemical hypogonadism seems always to increase with advancing age, being independently from the study considered, at the lowest in men younger than 49 y and progressively increasing through decades, with the highest prevalence being in men in their 80s.
Several cutoffs for male hypogonadism have been suggested on the basis of the of these large cohort studies. The comparison of such kind of large cohort studies clearly remarks the great heterogeneity of outcomes, which differ for each study according to the peculiarity of the study de and the and type of clinical and laboratory data collected. While changes in circulating total, free, and bioavailable T, E 2and SHBG are unidirectional in almost all the studies, several other outcomes were not replicated, thus leading to conflicting when different studies are compared each other Table 3Table 4.
The relationship between the decline of serum T and the worsening of sexual function has been investigated and confirmed by most of these studies Table 3. Changes in body composition lead to an increased risk of developing both the metabolic syndrome dyslipidemia, 65, and diabetes Table 3. The EMAS study showed that weight loss is associated to an increase, while weight gain to a decrease in both total and free serum T, with the same association persisting by considering waist circumference 82 As ly reported, obesity probably determines an impairment of the hypothalamic-pituitary function, leading to lower LH incretion and finally to hypogonadotropic hypogonadism.
This evidence is very important because it suggests that weight management and obesity avoidance could be useful to prevent T decline. The major role of serum estrogens on bone health has been suggested by almost all the studies, serum E 2 and T being directly correlated with bone mineral density BMD.
This correlation is particularly strong for free serum E 2 86, Furthermore, the MrOS has shown that low serum T together with high SHBG levels and low serum estradiol levels are associated with increased risk of non-vertebral fracture. Low total T levels were associated with lower hemoglobin levels in the InCHianti study similarly to EMAS, 89 suggesting that the effects of low T on hemoglobin should be carefully evaluated in older men due to the fact that anemia is one of the strongest markers of frailty Older women sex Norman nm all studies investigated physical performance and both the muscular mass and strength in relation to circulating sex steroids.
Physical performance was only weakly associated to serum T in the MMAS In regard to body composition, total serum T is related directly to lean mass, playing a possible protective role in healthy aging, since a better muscular function helps preventing falls, fractures, and frailty to some extent, as suggested by the MrOS study. Otherwise, in the MMAS a good health and the absence of chronic illness were both associated with a less important decline of serum T 37 Table 3.
Not all the studies investigated neuropsychological correlates of age-related T decline. The BLSA studied the possible correlation between androgens and cognitive function leading to a possible role of T in preventing cognitive dysfunction and depressive mood. In the MrOS the mortality risk appeared to be higher when also low serum E 2 was present. The integrated analysis of data provided by these large longitudinal studies allows highlighting several issues that are of concern for research advancement, methodological outcome and finally for clinical practice.
At the beginning most of these longitudinal studies provided first analyses based on cross-sectional data. First cross-sectional data did not find changes in circulating sex steroids between older and younger participants. Accordingly, the most important result reached by all the studies is to demonstratethe serum T decline with advancing age.
Particularly, both free and total serum T levels tend to decrease; the latter decreases lesser than the former as a consequence of the progressive increase of SHBG with aging Table 4. In all studies that have investigated male sexuality, serum T resulted inversely related to sexual desire and to some extent to sexual activity and erectile function too Table 4.
Another concordant result is the association between low serum T and obesity, metabolic comorbidities such as the metabolic syndrome, and type 2 diabetes Table 4. Among other clinical aspects that are associated to serum T lowering with advancing age, all-cause mortality, body composition changes, especially overweight ad obesity as well as metabolis syndrome and diabetes, all have been over and over again associated to T decline in aging Table 4.
The methodological approach used for T measurement has changed overtime according to advancements in this field in all the studies Table 4. This implies that the comparison of the coming from different studies as well as the of the same study obtained in different periods by using different assay methods remain challenging. There is not consensus about the correlation between total serum T measured by MS and IAs among studies since some studies find a good correlation while others find discordant measurements Table 4. This issue is important when data coming from research studies like these are transposed and applied to daily clinical practice since IAs are commonly employed, at present, in clinical laboratories.
The most controversial issues concern the association of T decline to impaired physical performance, neuropsychological issues, CV-related mortality, and cancer risk Table 4. Table 4 summarizes in detail the main analogies and discrepancies regarding the issues that have been mostly investigated by large cohort studies till now Table 4. The decline of serum T with advancing age has been traditionally interpreted as the male counterpart of menopause.
In other words, the decrease of T was considered as a condition due to the aging of gonadal function. In this old view, the term andropause was considered as a physiological event like menopause in females with the unique difference that the ovaries stop to function suddenly while the testes loose their function gradually Fig. At present, it has not defined whether the decline of serum T in the elderly represents a physiological process of aging or whether this event should be considered as pathological.
With this in view, the identification of patients with low serum T that might beneficiate of replacement therapy on one hand and the recognition of those for which therapy is not indicated is challenging. All these issues usually converge on the practical point concerning how to diagnose LOH. Recently, there is consensus among endocrinologists, andrologists, and urologists about the fact that the finding of biochemical T deficiency does not necessarily correspond to LOH in middle-aged-to-older men.
Furthermore, among aging men is quite common a condition of compensated hypogonadism, represented by normal T levels with high gonadotropins levels, whose prevalence increases with aging and which seems to be a subclinical condition that could develop in overt, primary hypogonadism overtime 90 Fig. Recently, data coming from the EMAS study confirm that age is correlated with the development of primary hypogonadism, but not with secondary hypogonadism, the latter being strictly associated to comorbidities rather than age.
In younger men hypogonadism both hypergonadotropic and hypogonadotropic is usually due to well-known causes, which can be congenital or acquired, and the site of origin is easily recognizable. Other factors involved in serum T declining include bad lifestyle habits, such as smoking and excessive alcohol intake, and chronic therapies with opiates and glucocorticoids, increasingly used to treat elderly population Table 1. Overweight, obesity, and metabolic disorders metabolic syndrome, diabetes, dyslipidemia are more frequent in older men and are all associated to low serum T in men, as already discussed in this article.
Chronic liver diseases, especially cirrhosis and fatty liver disease, are associated to hypogonadism as a consequence of increased liver production of SHBG and of estrogen excess and its inhibitory effect on gonadotropins. Male hypogonadism is highly prevalent also in patients with chronic kidney disease as a consequence of testicular damage primary hypogonadism.
Finally, treatments used for systemic chronic diseases might induce hypogonadism as in the case of rheumatoid arthritis.
The issue concerning the relationship existing between morbidities and LOH is relevant since might to be bidirectional. By decreasing the activity of the pituitary-gonadal axis it is possible to reduce some body functions e. Serum T might fall down in patients with acute, critical illnesses and normal serum T levels are restored by the resolution of the acute clinical condition.
As mentioned above, patient's poor health status in terms of deteriorated clinical conditions might influence T secretion. In aging men, however, the more complicated, multidimensional concept named frailty should be also considered. Frailty is inversely related to serum T in older men, as substantiated by several studies. Data available on the relationship among aging, hypogonadism, and infectious diseases are scanty.
It is well known that sepsis induces a fall of serum T in men together with a decrease of serum LH, consisting with a condition of hypogonadotropic hypogonadism. The same hormonal change occurs in patients with other acute illnesses different from infectious diseases These changes seem to be part of a mechanism, which is adaptive to poor health status aiming to counteract the high catabolic state due to the acute, severe clinical condition.
Among infectious diseases that may interfere with circulating T, rare testicular infections causing orchitis usually induce a temporary or permanent primary hypogonadism hypergonadotropic hypogonadism. Among HIV infected-men a process of accelerated aging seems to take place, deriving from a multifactorial etiology immunosenescence, inflammation, multimorbidity ; therefore, HIV infection can be considered a model of premature aging. The diagnosis of hypogonadism in these patients shares all the problems physicians have with older men and it is even more difficult due to the fact that symptoms and s are much more less specific than in the general population.
and symptoms, especially those related to sexuality and body composition changes, overlap, in fact, with those of HIV infection. The cut-off of serum total T below which the diagnosis of overt biochemical hypogonadism could be formulated remains to be determined. When serum total T levels are borderline evaluation of free T can be useful, especially among older men who physiologically tend to have increased levels of SHBG 33, In particular, SHBG measurement is indicated in obese patients and patients with chronic diseases e. It is important to remark, however, that common laboratory assays used for free T measurement are not reliable and calculation of free T starting from total T, albumin and SHBG with equations that have been validated should be preferred.
Since very often the symptoms suggestive of low T are attributed to age among Older women sex Norman nm men, recognizing hypogonadism is not easy. The interview is essential in order to disclose symptoms of hypogonadism, which belong mainly to sexual and physical functions. The most specific symptoms related to the decrease of serum T are: reduced sexual desire libido and activity, decreased spontaneous erections in the morning, erectile dysfunction, reduced shaving frequency, decreased energy and vitality, and occasionally hot flushes 3,12,25,49, Fig.
Other symptoms are less specific e.Older women sex Norman nm
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Aging and sex hormones in males