title: A randomized placebo-controlled trial of short-term graded transdermal estradiol in healthy gonadotropin-releasing hormone agonist-suppressed pre- and postmenopausal women: effects on serum markers of bone turnover, insulin-like growth factor-I, and osteoclastogenic mediators.
abstract: The acute effects of estradiol on procollagen type 1 formation in pre- and postmenopausal women are controversial. Twenty-three premenopausal women and 13 postmenopausal women received two consecutive im injections of 3.75 mg leuprolide acetate 3 wk apart to block endogenous ovarian steroidogenesis. Transdermal estradiol therapy commenced on the night of the second leuprolide injection in all subjects, except five pre- and two postmenopausal women who were randomized to receive placebo patches. Estradiol therapy was applied incrementally, with each dose of 0.05, 0.10, 0.15, and 0.20 mg/d administered for 4 consecutive days, to mimic the estradiol changes typifying the follicular phase of the menstrual cycle. Blood aminoterminal propeptide of type I procollagen (PINP), intact osteocalcin (OC), carboxyterminal telopeptide of type I collagen (CTx), IGF-I, and estradiol were measured before and at the end of each estradiol increment. Potential mediators such as osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) were also measured. Despite comparable increases in serum estradiol, PINP increased more in postmenopausal compared with premenopausal women (between-group P = 0.03) and occurred at a time when CTx and OC did not change. CTx and IGF-I changed minimally and inconsistently, whereas OC, RANKL, and osteoprotegerin were stable. Repeated measures linear regression disclosed a significant negative association between increases in estradiol and PINP in premenopausal women (P = 0.0006) only. This suggests that lower dose estradiol should greatly increase PINP. Analogous regressions also showed significant negative relationships between changes in estradiol and RANKL in both pre- (P = 0.04) and postmenopausal (P = 0.002) women. Changes in serum markers of bone formation (PINP or OC) did not correlate with those of IGF-I. We conclude that lower dose estradiol rapidly increases osteoblastic collagen synthesis in women at a time when collagen degradation is stable and that this response differs between pre- and postmenopausal women. The effect of estradiol on bone formation does not appear to be mediated by IGF-I. In contrast, RANKL is likely to mediate the effect of estradiol on osteoclastogenesis.
authors.affiliation: Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Liu
authors.forename: Kelley A
authors.initials: KA
authors.lastname: Hoey
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Mielke
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D001862:Bone Resorption / Q000097:blood; D002352:Carrier Proteins / Q000097:blood; D024042:Collagen Type I / Q000097:blood; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D016729:Leuprolide / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000097:blood; D008593:Menopause / Q000097:blood; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis / Q000187:drug effects*; D053244:Osteoprotegerin; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood; D018124:Receptors, Tumor Necrosis Factor
chemical_list: D002352:Carrier Proteins; D024042:Collagen Type I; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D010446:Peptide Fragments; D011347:Procollagen; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C047202:procollagen Type I N-terminal peptide; D015675:Osteocalcin; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D016729:Leuprolide