The acute effects of estradiol on procollagen type 1 formation in pre- and postmenopausal women are controversial. Twenty-three pre- and 13 postmenopausal women received two consecutive i.m. injections of 3.75 mg leuprolide acetate three weeks apart to block endogenous ovarian steroidogenesis. Transdermal estradiol therapy commenced on the night of the second leuprolide injection in all except 5 pre- and 2 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 per day 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 crosslinked 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 (OPG) and RANK ligand (RANKL) were also measured. Despite comparable increases in serum estradiol, PINP increased more in post 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 OPG 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 more 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 is not mediated by IGF-I. In contrast, RANKL is likely to mediate the effect of estradiol on osteoclastogenesis.