madman
Super Moderator
Abstract
Purpose Symptoms of hypogonadism are often reported by subjects with normal serum testosterone (T) levels. We aimed to assess the association between clinical symptoms in andrological outpatients and sex steroids levels.
Methods This is a retrospective cross-sectional cohort study in an Academic clinic and research unit. International Index of Erectile Function (IIEF, EF domain) and Aging Males Symptoms scale (AMS) questionnaires were completed by 635 and 574 men, respectively (mean age: 47.3±13.9 and 47.4±13.8 years, p=0.829), free of interfering medications with complaints possibly related to hypogonadism.
Results Serum total/free T, as well as dihydro-T (DHT), was associated with IIEF-EF and AMS scores in the overall population using univariate analyses. Multivariate approaches revealed DHT concentrations in subjects with normal T levels (n=416, Total T>12 nmol/L) to be significant predictors of AMS scores. A 0.1 nmol/l serum DHT increase within the eugonadal range was associated with a 4.67% decrease in odds of having worse symptoms (p=0.011). In men with biochemical hypogonadism (Total T<12 nmol/L), total and free T rather than DHT were associated with AMS results. This association was not found for IIEF-EF scores. Indirect effects of age and BMI were seen for relations with hormone concentrations but not questionnaire scores.
Conclusion DHT can be associated with symptoms of hypogonadism in biochemically eugonadal men. Serum DHT measurement might be helpful once the diagnosis of hypogonadism has been ruled out but should not be routinely included in the primary diagnostic process.
Introduction
Treatment of male hypogonadism has been one of the most controversial topics in endocrinology during the last few years. Several studies have rekindled scientific interests on the side effects and benefits of testosterone (T) administration [1] and have had their coronation in the Testosterone Trials, a series of seven placebo-controlled, double-blind trials in elderly hypogonadal subjects [2]. Most of the reported side effects of T administration had occurred in subjects with high baseline serum T—i.e., subjects who should not have received any kind of androgen replacement therapy—in the hope of improving sexual health and/or physical function. This has led to an FDA warning allowing the use of T only in cases of confirmed low T levels and only in “men with disorders of the testicles, pituitary gland, or brain that cause hypogonadism”, as to avoid “attempts to relieve symptoms in men who have low T for no apparent reason other than aging”. Apparently, this addresses men with so-called functional hypogonadism, a condition associated with comorbidities such as obesity/type 2 diabetes mellitus. The T-Trials were performed in elderly men with functional hypogonadism and demonstrated benefits in several dimensions of symptoms [2]. Accordingly, guidelines for the treatment of men with functional hypogonadism have recently been published [3.
Signs and symptoms associated with hypogonadism [4–6] are largely variable: the most common ones, such as fatigue, impaired erectile function and reduced sexual drive, might be the result of several other conditions and are often disregarded as “common features of aging” by patients and clinicians alike [7, 8]. However, signs and symptoms of hypogonadism are mandatory for diagnosis, together with biochemical confirmation of T deficiency [4–6, 9], and should not be overlooked. Testosterone treatment should be considered following diagnosis confirmation, to improve sexual and non-sexual symptoms of hypogonadism [10, 11].
Androgen action is mediated through the androgen receptor (AR); changes in its structure lead to different clinical phenotypes, ranging from complete androgen insensitivity syndrome (CAIS) to apparently normal males [12]. Polymorphisms of the AR gene CAG repeats have also been associated with symptoms of aging in men, namely those of psychological nature [13] but also worse sexual function [14, 15]. While T is undoubtedly the most important androgen, it is worth remembering that the AR also binds its metabolite, 5α-dihydrotestosterone (DHT). T is irreversibly converted to DHT by the microsomal enzyme 5α-reductase, which exists in 3 isoforms present in multiple tissues of the male body (type I: in brain, liver, muscle, skin, and prostate; type II: in epididymis, hair follicles, liver, prostate, and seminal vesicles; type III: in brain, heart, lung, pancreas, colon, stomach, liver, muscle, prostate, and testes).
This leads to measurable serum levels of DHT, which, at least to a certain extent, reflect its biological activity in the overall male organism [16]
Compared to DHT, T has a twofold lower affinity to the AR and a fivefold faster dissociation rate [12], which is largely compensated by significantly higher serum concentrations. While T is secreted under the direct stimulus of pituitary LH, in turn, secreted following hypothalamic GnRH stimulus [17, 18], the only regulating factor for DHT conversion is the expression of the 5-alpha-reductase genes and the activity of the isoforms of the transcribed enzyme. In hair follicles increased expression patterns for both 5αR2 and AR has been associated with androgenetic alopecia [19] and treatment of androgenetic alopecia with 5α-reductase inhibitors (5ARIs) such as finasteride is a definite proof of the involvement of DHT in clinical manifestations of androgen activity as well as side effects of 5ARIs (such as impaired sexual function and more frequent psychological and cognitive complaints), putatively inhibiting especially the cerebral 5αR3 isomer [20–24].
Mutations in the 5αR2-gene lead to the severe phenotype of pseudohermaphroditism [25–28]. Vice versa, treatment of symptoms of classical hypogonadism might be possible using pure DHT [29], this especially being the case in regard to male sexual function [30].
Nevertheless, it should be debated that a non-aromatizable androgen might have a long-term negative impact on bone integrity.
Based on these assumptions, we hypothesize that in some patients presenting with classical signs and symptoms of male hypogonadism, there might be an association of DHT levels within the setting of the normal range of total T concentrations in serum with these specific complaints. This would be a clinical picture similar to the side effects of 5ARIs [24], but not owing to this medication but due to other conditions. To assess this, we retrospectively reviewed patient charts in the electronic database Androbase [31] of the Center of Reproductive Medicine and Andrology (CeRA) in Münster (Germany).
Conclusions
The presence of symptoms of hypogonadism with biochemically normal levels of T but low concentrations of DHT is, according to our results, a matter for discussion.
Once biochemical hypogonadism has been excluded, DHT can be a useful addition to the endocrine assessment of subjects complaining of symptoms traditionally associated with androgen deficiency.
Our results contribute to the observations by which 5-alpha-reductase inhibitors can affect male sexual function even within the eugonadal range of T.
Purpose Symptoms of hypogonadism are often reported by subjects with normal serum testosterone (T) levels. We aimed to assess the association between clinical symptoms in andrological outpatients and sex steroids levels.
Methods This is a retrospective cross-sectional cohort study in an Academic clinic and research unit. International Index of Erectile Function (IIEF, EF domain) and Aging Males Symptoms scale (AMS) questionnaires were completed by 635 and 574 men, respectively (mean age: 47.3±13.9 and 47.4±13.8 years, p=0.829), free of interfering medications with complaints possibly related to hypogonadism.
Results Serum total/free T, as well as dihydro-T (DHT), was associated with IIEF-EF and AMS scores in the overall population using univariate analyses. Multivariate approaches revealed DHT concentrations in subjects with normal T levels (n=416, Total T>12 nmol/L) to be significant predictors of AMS scores. A 0.1 nmol/l serum DHT increase within the eugonadal range was associated with a 4.67% decrease in odds of having worse symptoms (p=0.011). In men with biochemical hypogonadism (Total T<12 nmol/L), total and free T rather than DHT were associated with AMS results. This association was not found for IIEF-EF scores. Indirect effects of age and BMI were seen for relations with hormone concentrations but not questionnaire scores.
Conclusion DHT can be associated with symptoms of hypogonadism in biochemically eugonadal men. Serum DHT measurement might be helpful once the diagnosis of hypogonadism has been ruled out but should not be routinely included in the primary diagnostic process.
Introduction
Treatment of male hypogonadism has been one of the most controversial topics in endocrinology during the last few years. Several studies have rekindled scientific interests on the side effects and benefits of testosterone (T) administration [1] and have had their coronation in the Testosterone Trials, a series of seven placebo-controlled, double-blind trials in elderly hypogonadal subjects [2]. Most of the reported side effects of T administration had occurred in subjects with high baseline serum T—i.e., subjects who should not have received any kind of androgen replacement therapy—in the hope of improving sexual health and/or physical function. This has led to an FDA warning allowing the use of T only in cases of confirmed low T levels and only in “men with disorders of the testicles, pituitary gland, or brain that cause hypogonadism”, as to avoid “attempts to relieve symptoms in men who have low T for no apparent reason other than aging”. Apparently, this addresses men with so-called functional hypogonadism, a condition associated with comorbidities such as obesity/type 2 diabetes mellitus. The T-Trials were performed in elderly men with functional hypogonadism and demonstrated benefits in several dimensions of symptoms [2]. Accordingly, guidelines for the treatment of men with functional hypogonadism have recently been published [3.
Signs and symptoms associated with hypogonadism [4–6] are largely variable: the most common ones, such as fatigue, impaired erectile function and reduced sexual drive, might be the result of several other conditions and are often disregarded as “common features of aging” by patients and clinicians alike [7, 8]. However, signs and symptoms of hypogonadism are mandatory for diagnosis, together with biochemical confirmation of T deficiency [4–6, 9], and should not be overlooked. Testosterone treatment should be considered following diagnosis confirmation, to improve sexual and non-sexual symptoms of hypogonadism [10, 11].
Androgen action is mediated through the androgen receptor (AR); changes in its structure lead to different clinical phenotypes, ranging from complete androgen insensitivity syndrome (CAIS) to apparently normal males [12]. Polymorphisms of the AR gene CAG repeats have also been associated with symptoms of aging in men, namely those of psychological nature [13] but also worse sexual function [14, 15]. While T is undoubtedly the most important androgen, it is worth remembering that the AR also binds its metabolite, 5α-dihydrotestosterone (DHT). T is irreversibly converted to DHT by the microsomal enzyme 5α-reductase, which exists in 3 isoforms present in multiple tissues of the male body (type I: in brain, liver, muscle, skin, and prostate; type II: in epididymis, hair follicles, liver, prostate, and seminal vesicles; type III: in brain, heart, lung, pancreas, colon, stomach, liver, muscle, prostate, and testes).
This leads to measurable serum levels of DHT, which, at least to a certain extent, reflect its biological activity in the overall male organism [16]
Compared to DHT, T has a twofold lower affinity to the AR and a fivefold faster dissociation rate [12], which is largely compensated by significantly higher serum concentrations. While T is secreted under the direct stimulus of pituitary LH, in turn, secreted following hypothalamic GnRH stimulus [17, 18], the only regulating factor for DHT conversion is the expression of the 5-alpha-reductase genes and the activity of the isoforms of the transcribed enzyme. In hair follicles increased expression patterns for both 5αR2 and AR has been associated with androgenetic alopecia [19] and treatment of androgenetic alopecia with 5α-reductase inhibitors (5ARIs) such as finasteride is a definite proof of the involvement of DHT in clinical manifestations of androgen activity as well as side effects of 5ARIs (such as impaired sexual function and more frequent psychological and cognitive complaints), putatively inhibiting especially the cerebral 5αR3 isomer [20–24].
Mutations in the 5αR2-gene lead to the severe phenotype of pseudohermaphroditism [25–28]. Vice versa, treatment of symptoms of classical hypogonadism might be possible using pure DHT [29], this especially being the case in regard to male sexual function [30].
Nevertheless, it should be debated that a non-aromatizable androgen might have a long-term negative impact on bone integrity.
Based on these assumptions, we hypothesize that in some patients presenting with classical signs and symptoms of male hypogonadism, there might be an association of DHT levels within the setting of the normal range of total T concentrations in serum with these specific complaints. This would be a clinical picture similar to the side effects of 5ARIs [24], but not owing to this medication but due to other conditions. To assess this, we retrospectively reviewed patient charts in the electronic database Androbase [31] of the Center of Reproductive Medicine and Andrology (CeRA) in Münster (Germany).
Conclusions
The presence of symptoms of hypogonadism with biochemically normal levels of T but low concentrations of DHT is, according to our results, a matter for discussion.
Once biochemical hypogonadism has been excluded, DHT can be a useful addition to the endocrine assessment of subjects complaining of symptoms traditionally associated with androgen deficiency.
Our results contribute to the observations by which 5-alpha-reductase inhibitors can affect male sexual function even within the eugonadal range of T.
