Androgens in Health and Disease.pdf - E Library

Chapter 5/Estrogen Action in Males 93
numbers of dopaminergic neurons. Thus, it appears that masculinization (or
defeminization) of the AvPV requires activation of ERα, presumably during development,
in order to induce cell death in the AvPV of male mice (34).
Regulation of the “tonic” pattern of LH secretion in adult male vertebrates clearly
relies on negative feedback by T. Castration results in dramatic increases in serum LH,
whereas T replacement reinstates or maintains negative feedback on LH synthesis and
secretion (6,35). A number of studies demonstrated that E 2 treatments can suppress LH
levels in castrated male mice and rats, but dihydrotestosterone (DHT) can also suppress
serum LH in some studies in male rodents (6,35,36). Thus, it appears that there
may be some degree of redundancy in the receptor paths by which T regulates LH
synthesis and secretion.
Characterizations of models of androgen insensitivity, estrogen insensitivity, and estrogen
insufficiency further supports the notion of redundant receptor pathways involved in
T regulation of LH in males. For instance, serum LH and T levels are elevated in Tfm mice
(37) and Tfm rats (38,39) and there are some cases of androgen insensitivity in humans
(40). However, serum LH levels are also elevated in the only known ERα-deficient male
patient (41) and one aromatase-deficient male patient (42), whereas a second aromatase
deficient adult male patient exhibited only slight elevations in serum LH (43). These data
suggest that AR pathways play a significant role in mediating the negative feedback effects
of T on LH but that aromatization and activation of ERα also plays a role.
Several lines of evidence from the αERKO model further support a role for both ERα
and AR in regulating LH. First, serum LH and T levels are only slightly elevated (twofold)
in adult αERKO males despite complete E 2 insensitivity (35,36). Second, castration
results in dramatic elevations of LH levels in both WT and αERKO males and E 2
treatments suppress the postcastration rise in serum LH in WT males but not in αERKO
males. Third, T or DHT treatments will partly suppress the postcastration rise in serum
LH in αERKO males. Thus, AR signaling is sufficient to maintain relatively normal
serum LH levels in the absence of intact ERα signaling, but ERα pathways can also
effectively suppress synthesis and secretion of LH in WT males. Furthermore, the estrogen
insensitivity observed in αERKO males coupled with normal serum LH values in
βERKO males suggest that ERβ does not play a significant role in mediating negative
feedback effects on LH synthesis and secretion in males.
Testicular feedback regulation of follicle-stimulating hormone (FSH) is more complicated
and involves a combination of testicular T and testicular inhibin. It appears that
there may be some species differences in the degree of dependence on estrogen and ER
vs inhibin regulation of FSH in male rodents and primates. For instance, aromatasedeficient
and ERα-deficient humans exhibit elevated FSH (41,42), whereas ARKO and
αERKO males exhibit normal serum FSH levels (22,35,44,45). This implies that testicular
inhibin may play a more important role in rodent models. Indeed, castration causes
significant elevations of serum FSH in both WT and αERKO males, whereas E 2 or T
treatments suppress serum FSH only in the castrated WT (35), suggesting that aromatization
and activation of ERα plays a role in suppression of FSH in normal WT male
mice. The fact that T and DHT treatments failed to suppress serum FSH in castrated
αERKO males further suggests that the normal serum FSH levels observed in intact
αERKO males are the result of the feedback effects of testicular inhibins (35). Thus,
although both inhibins and T regulate FSH in humans and mice, it appears that inhibin
feedback more effectively substitutes for deficiencies in estrogen signaling in mice.