Regulation of bone turnover by sex steroids in men.
BACKGROUND
The mechanism(s) by which sex steroids regulate bone turnover in humans are unclear, and recent studies have suggested that follicle-stimulating hormone (FSH) may play an important role in regulating bone resorption.


METHODS
Fifty-nine men (median age, 69 yr) underwent suppression of sex steroids using a gonadotropin-releasing hormone (GnRH) agonist and aromatase blocker and were replaced with testosterone (T; 5 mg/d) and estradiol (E; 37.5 microg/d). After assessment of bone resorption markers (serum C-terminal telopeptide of type I collagen [CTX] and TRACP5b), they were randomized to sex steroid deficiency (-T, -E), E alone (-T, +E), T alone (+T, -E), or both (+T, +E) and restudied 3 wk later. Bone marrow aspirates were obtained to isolate osteoblastic, T, and monocytic cells using magnetic-activated cell sorting.


RESULTS
Serum CTX and TRACP5b increased significantly (by 71% and 15%, p < 0.01 and < 0.001, respectively) in the -T, -E group, and these increases occurred despite a 60% suppression of serum FSH levels (p < 0.001) caused by the GnRH agonist. There were significant E (but not T) effects on preventing increases in serum CTx and TRACP levels. There was a nonsignificant trend (p = 0.122) for E to suppress RANKL mRNA levels in bone marrow osteoblastic cells. Changes in mRNA levels for other cytokines (TNF-alpha, interleukin (IL)-1alpha, IL-1beta, IL-1ra, IFN-gamma) in bone marrow cells were not significant.


CONCLUSIONS
E has greater suppressive effects on bone resorption than T, and increased bone resorption after sex steroid deficiency can occur independently of changes in FSH secretion. E effects on bone resorption may be mediated by regulation of RANKL production by osteoblastic cells, although further studies using more highly purified cells may reduce the variability of the mRNA measurements and allow for clearer definition of the mediators of sex steroid action in vivo.
Sanyal
Arunik
A
Endocrine Research Unit, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Hoey
Kelley A
KA
Mödder
Ulrike I
UI
Lamsam
Jesse L
JL
McCready
Louise K
LK
Peterson
James M
JM
Achenbach
Sara J
SJ
Oursler
Merry Jo
MJ
Khosla
Sundeep
S
D000368:Aged; D000369:Aged, 80 and over; D016723:Bone Remodeling; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D053245:RANK Ligand / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
D053245:RANK Ligand; D012333:RNA, Messenger; C505688:TNFSF11 protein, human; D005640:Follicle Stimulating Hormone