Androgens in Health and Disease.pdf - E Library

Chapter 1/Testosterone Synthesis, Transport, and Metabolism 11
Estradiol also reduces LH pulse amplitude in men (79) and suppresses GnRH-stimulated
LH secretion in primate pituitary cells (85), indicating a pituitary site of action.
Follicle-stimulating hormone secretion is also suppressed following testosterone and
estradiol administration (86,93) because FSH production, like LH, production is GnRH
dependent. In addition, FSH is negatively regulated at the level of the gonadotroph by
testicular inhibin-B (94). A schematic of the interrelationship between gonadotropin and
testosterone secretion is shown in Fig. 3.
CIRCULATING TESTOSTERONE CONCENTRATIONS
The usual normal range for testosterone levels in serum samples drawn in the morning
from adult men is 3–10 ng/mL (10–40 nM), whereas following bilateral orchidectomy,
the level of testosterone declines to less than 0.3 ng/mL. The blood production rate of
testosterone in normal adult men is estimated to range from 5000 to 7500 µg/24 h (95).
The testosterone content of the adult human testis is only about 50 µg (1 µg/g testis),
indicating that nearly all of the synthesized testosterone is released into the circulation.
Steroid hormones are presumed to diffuse freely and rapidly across cell membranes. As
such, following its synthesis, testosterone exits the Leydig cell to enter the testicular
interstitial compartment and diffuse across the capillary endothelium into the circulation
to produce a secretory pulse. Interestingly, the LH receptor is found in testicular vascular
endothelium (96), where it could have a vasoactive function and facilitate diffusion.
In many species, including rams, dogs, and nonhuman primates, frequent blood
sampling reveals a tight coupling between LH pulses and testosterone secretory episodes
with a lag of about 30 min. In men, however, episodes of testosterone secretion
are more difficult to identify by visual inspection in plasma concentration profiles (97),
although, as shown in Fig. 4, hourly testosterone secretory episodes are readily apparent
in sequential samples of spermatic vein blood (98). The inability to readily identify
testosterone secretory episodes in human peripheral blood samples may relate in part
to a rapid pulse frequency, because slowing the GnRH pulse generator, as with
fluoxymesterone (99), unmasked the circulating testosterone response to LH. However,
even under those conditions, testosterone secretory episodes were delayed and
prolonged and of relatively low magnitude. Thus, other factors, such as Leydig cell
responsiveness to LH and testosterone clearance, appear to contribute to the configuration
of the testosterone pulse in men.
Frequent sampling of human spermatic vein blood revealed that the testis secretes
pulses of the testosterone precursor steroids, including pregnenolone, 17-hydroxypregnenolone,
DHEA, progesterone, 17-hydroxyprogesterone, and androstenedione
together with testosterone, as shown in Fig. 4. Moreover, the relative concentration of
these steroids in spermatic vein blood was proportional to their intratesticular concentration
(100). One idea is that these precursor steroids are secreted as unnecessary
byproducts in the transformation of pregnenolone to testosterone, because none is known
to have a physiological function in males.
There is also a diurnal variation in circulating testosterone levels in adult men, with
highest levels in the early morning, followed by a progressive fall throughout the day,
to nadir levels in the evening and during the first few hours of sleep (101). Peak and nadir
values differ by approx 15%, although more pronounced differences are sometimes
observed (102). Although a rise in LH precedes the nocturnal rise in testosterone levels
in pubertal boys (103), there is no clear diurnal rhythm for LH in most adult men (104),