Testis dysfunction can weaken bone and reduce muscle mass as well as impair sexual function. Testosterone (T) therapy has useful effects on sex organs, bone, and muscle in T-deficient males, but prostate concerns can preclude T use in some men. Although estrogens or other drugs can protect bone in men, gynecomastia makes estrogens unappealing, and other drugs may also be undesirable in some cases. Selective estrogen receptor modulators (SERMs) inhibit estrogen-evoked sex organ growth but mimic estrogen effects on bone and cholesterol and are advantageous for some women. SERMs may also be useful in men who must avoid androgens. As a preclinical test of this idea, tamoxifen (a SERM) and testosterone propionate (TP, a classic androgen) were compared for their efficacy in preventing varied effects of orchidectomy (ORX) in adult male rats. ORX led to ventral prostate and seminal vesicle atrophy and decreases in somatic growth, proximal tibia bone mineral density (BMD), and serum growth hormone (GH) and insulin-like growth factor I (IGF-I). ORX also increased anterior pituitary glandular kallikrein, serum cholesterol, and body temperature. Pituitary prolactin (PRL) content was unaltered. ORX effects on sex organs, somatic growth, IGF-I, cholesterol, body temperature, and pituitary kallikrein were prevented by TP at 1 mg/kg (3 doses per week), but BMD and GH were unresponsive. ORX effects on BMD and GH were prevented by TP at 10 mg/kg, but this dose evoked supraphysiologic increases in sex organs and PRL, failed to restore somatic growth, and further reduced IGF-I. Tamoxifen (1 mg/kg daily) prevented ORX effects on BMD, GH, and cholesterol without altering basal or TP-induced sex organ growth and further reduced IGF-I and somatic growth. Tamoxifen did not alter basal PRL but blocked increases caused by TP at 10 mg/kg. In summary, tamoxifen prevented ORX effects on bone and cholesterol in male rats without affecting sex organs or PRL and might be useful for men who must avoid androgens. Unexpectedly, a TP dose that replicated testis effects on sex organs and other targets had no effect on BMD or GH, and a larger TP dose that restored BMD and GH was worse at replicating normal male physiology. In addition, correlation/regression results suggested that the GH-IGF-I axis contributes to changes in BMD.

Estrogen (E) and T(3) regulate gene expression by receptor mechanisms that may enable hormonal interplay affecting growth and metabolism. Prior studies of E and tamoxifen (TM) interplay with T(3) in female rats identified a subset of E responses that required T(3) for expression and exhibited large agonist responses to TM. In contrast, TM acted more like an antagonist in most T(3)-independent E responses. This study used male rats to further explore the role of T(3) in E effects on growth and metabolism, and the relation of such effects to changes in serum GH and IGF-I. Orchidectomized, hypothyroid rats were treated 6 wk with vehicle, E2 benzoate (E2B), or TM with or without T(3). The following parameters were measured: body weight change; tibia length and bone mineral density; heart and kidney weight; food intake and body temperature; serum levels of glucose, cholesterol, triglycerides, GH, and IGF-I; seminal vesicle weight; and anterior pituitary levels of GH, PRL, glandular kallikrein, and total protein. Interplay with T(3) contributed to multiple E effects on growth and metabolism, and some E responses involved both T(3)-dependent and T(3)-independent components. Both E2B and TM increased serum GH, but the increases were poorly coupled to IGF-I. Correlation/regression analysis of individual rat data sets suggested distinct roles for GH and IGF-I in specific E effects. E2B and TM effects on somatic growth exhibited positive correlations with IGF-I and negative correlations with GH; effects on bone mineral density and triglycerides exhibited positive correlations with GH and negative correlations with IGF-I. Three pharmacologically distinct classes of in vivo E responses were identified in this study, and TM displayed a profile of biological activity that may be useful for men undergoing androgen-deprivation therapy.

Tamoxifen is a selective estrogen receptor (ER) modulator, but it is also a deactivating ligand for estrogen-related receptor-␥ (ERR␥) and a full agonist for the G protein-coupled estrogen receptor (GPER). Fulvestrant is a selective ER down-regulator that lacks agonist effects on ER␣/ER␤, is inactive on ERR␥, but acts as a full agonist on GPER. Fulvestrant effects on tamoxifen actions on uterine and somatic growth, bone, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and pituitary prolactin were analyzed to pharmacologically discriminate tamoxifen effects that may be mediated by ER␣/ER␤ versus ERR␥ versus GPER. Ovariectomized rats received tamoxifen (0.6 mg/kg/daily) plus fulvestrant at 0, 3, 6, or 12 mg/kg/daily for 5 weeks; controls received vehicle or 6 mg/kg fulvestrant daily. Tamoxifen effects to increase uterine weight, decrease serum IGF-I, increase pituitary prolactin, and increase bone mineral density could be fully blocked by fulvestrant, indicating mediation by ER␣/ER␤. Tamoxifen effects to decrease pituitary GH, tibia length, and body weight were only partially blocked by fulvestrant, indicating involvement of mechanisms unrelated to ER␣/ER␤. Fulvestrant did not inhibit tamoxifen actions to reduce total pituitary protein, again indicating effects not mediated by ER␣/ER␤. Tamoxifen actions to reduce serum GH were mimicked rather than inhibited by fulvestrant, pharmacological features consistent with GPER involvement. However, fulvestrant alone increased IGF-I and also blocked tamoxifen-evoked IGF-I decreases; thus fulvestrant effects on serum GH might reflect increased IGF-I feedback inhibition. Fulvestrant alone had no effect on the other parameters. The findings indicate that mechanisms unrelated to ER␣/ER␤ contribute to tamoxifen effects on body weight, bone growth, and pituitary function. IntroductionTamoxifen is an estrogen receptor (ER) ligand that is characterized as a selective ER modulator (SERM); it acts as estrogen agonist on some targets while acting as an antagonist or partial agonist on others. This is not attributed to differing pharmacological actions on ER␣ versus ER␤, but reflects the diversity of mechanisms mediating ER actions at different targets.In classic models of ER function, estrogen binding to the ligand-binding domain (LBD) transforms ER conformation and enhances ER binding to specific target gene DNA sequences (McDonnell et al., 2002;Smith and O'Malley, 2004). One or both of two ER transactivation domains (AF-1 and AF-2) then bind coactivator proteins that alter gene transcription via the recruitment of chromatin-remodeling complexes and other factors. AF-1 is located in the ER N terminus and is ligand-independent, whereas AF-2 in the LBD is ligand-dependent. Involvement of AF-1 or AF-2 in estrogen responses varies from target to target depending on the genes, cell types, coactivators, and other signaling systems involved.SERMs transform ER conformation in a manner that activates DNA binding and AF-1-dependent gene expression in classic models o...

Estrogen (E) and T(3) regulate gene expression by receptor mechanisms that may enable hormonal interplay affecting growth and metabolism. Prior studies of E and tamoxifen (TM) interplay with T(3) in female rats identified a subset of E responses that required T(3) for expression and exhibited large agonist responses to TM. In contrast, TM acted more like an antagonist in most T(3)-independent E responses. This study used male rats to further explore the role of T(3) in E effects on growth and metabolism, and the relation of such effects to changes in serum GH and IGF-I. Orchidectomized, hypothyroid rats were treated 6 wk with vehicle, E2 benzoate (E2B), or TM with or without T(3). The following parameters were measured: body weight change; tibia length and bone mineral density; heart and kidney weight; food intake and body temperature; serum levels of glucose, cholesterol, triglycerides, GH, and IGF-I; seminal vesicle weight; and anterior pituitary levels of GH, PRL, glandular kallikrein, and total protein. Interplay with T(3) contributed to multiple E effects on growth and metabolism, and some E responses involved both T(3)-dependent and T(3)-independent components. Both E2B and TM increased serum GH, but the increases were poorly coupled to IGF-I. Correlation/regression analysis of individual rat data sets suggested distinct roles for GH and IGF-I in specific E effects. E2B and TM effects on somatic growth exhibited positive correlations with IGF-I and negative correlations with GH; effects on bone mineral density and triglycerides exhibited positive correlations with GH and negative correlations with IGF-I. Three pharmacologically distinct classes of in vivo E responses were identified in this study, and TM displayed a profile of biological activity that may be useful for men undergoing androgen-deprivation therapy.