Appraising Testosterone Signaling

To date, the majority of clinical studies have used the total testosterone concentration to assess androgen-dependent negative feedback on the hypothalamic-pituitary unit (36,37). However, in men, total testosterone is distributed in plasma as free (approx 2%), weakly albumin-bound (50-55%) and tightly globulin-bound (40-45%) steroid (116,117). Rapid dissociation of testosterone from low-affinity albumin (nominal unidirectional half-time 0.2 s at 37°C) would favor effectual tissue uptake within a brief (2 to 10 s) capillary transit time, so long as reassociation is minimized (118). On the other hand, slow release of testosterone from high-affinity SHBG (half-time 3.3 s at 37°C) would putatively restrict access to cells, at least when reassociation is limited. Protein-binding effects are important, because SHBG concentrations increase as much as twofold and bioavailable (non-SHBG-bound) testosterone concentrations fall by 30-50% in older individuals (20,119-122) (see Fig. 10A). Dynamic mechanisms of physiological control of free, SHBG- and Alb-bound testosterone are highlighted in the kinetic schema of Fig. 10B. Therefore, according to contemporary perspectives, carefully designed clinical studies will be needed to examine the age-dependence of free and bioavailable testosterone-mediated negative feedback on gonadotropin secretion (37).

Testosterone Levels Age

c LU

p < 0.0001 (Student's t-test) P < 0.01 (Wilcoxon)

1 1.579±0.041

□ ■

1

T

*

Older

Young

Older

Testosterone Levels

Fig. 9. (A) Notion of the approximate entropy (ApEn) statistic to quantitate relative regularity of serial (sample-by-sample) measurements. The bottom curve gives a cosine function (low ApEn) to illustrate a well-reproduced pattern, the middle curve shows partial degradation of regularity (intermediate ApEn), and the top frame depicts marked erosion of orderliness (high ApEn). (B) Increased ApEn of overnight (2.5-min) luteinizing hormone (LH) release profiles in healthy older compared with young men. Higher ApEn points to less orderly outflow of gonadotropin-releasing hormone (GnRH) and/or LH, or disruption of the GnRH-LH feedforward interface. Numerical values are the mean ± SEM. (C) Cross-approximate entropy (cross-ApEn) differences in older and young men. Differences exceeding three SEMs (older minus young) denote significant deterioration of young-adult coupling between oscillations of LH and testosterone (leftmost), LH and follicle-stimulating hormone (FSH), (left middle), LH and prolactin (PRL), (right middle), and LH and nocturnal penile tumescence (NPT) (rightmost). P values denote the probability of falsely rejecting the null hypothesis of equivalent two-hormone synchrony in the two age groups. (Unpublished compilation of data reported in refs. 30-32,95.)

Fig. 9. (A) Notion of the approximate entropy (ApEn) statistic to quantitate relative regularity of serial (sample-by-sample) measurements. The bottom curve gives a cosine function (low ApEn) to illustrate a well-reproduced pattern, the middle curve shows partial degradation of regularity (intermediate ApEn), and the top frame depicts marked erosion of orderliness (high ApEn). (B) Increased ApEn of overnight (2.5-min) luteinizing hormone (LH) release profiles in healthy older compared with young men. Higher ApEn points to less orderly outflow of gonadotropin-releasing hormone (GnRH) and/or LH, or disruption of the GnRH-LH feedforward interface. Numerical values are the mean ± SEM. (C) Cross-approximate entropy (cross-ApEn) differences in older and young men. Differences exceeding three SEMs (older minus young) denote significant deterioration of young-adult coupling between oscillations of LH and testosterone (leftmost), LH and follicle-stimulating hormone (FSH), (left middle), LH and prolactin (PRL), (right middle), and LH and nocturnal penile tumescence (NPT) (rightmost). P values denote the probability of falsely rejecting the null hypothesis of equivalent two-hormone synchrony in the two age groups. (Unpublished compilation of data reported in refs. 30-32,95.)

H ffl A

o CO

Si 400

3 co

200 350

Si 400

P= NS

-

O

1

384 ±26

S

i

308 1 42

V

X

(0-JD

Young

9

244114 S O

o

+

J 142116

-

t

(n-11)

Young

Older

P < 0.05

-

t

62 ±4.4

A

(n-11)

Older

Older

Fig. 10. (A) Comparison of serum total, non-sex hormone-binding globulin (SHBG) (bioavailable) and percentage free testosterone measurements in two cohorts of men; namely, young (n = 11) and older (n = 8). Similar mean total testosterone concentrations by age (top) belie a reduction in bioavailable and percentage non-SHBG-bound (percent free) testosterone (middle and lower) in older individuals. Adapted from ref. 32. (Figure continues)

B Leydig Cells

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