Physiological Versus Standard Sex Steroid Replacement In Young Women With Premature Ovarian Failure: Effects On Bone Mass Acquisition And Turnover Editorial Comment

It is well-recognized that young women with untreated premature ovarian failure (POF) are at increased risk of osteoporosis and bone fracture. Large, randomized trials have demonstrated that hormone replacement therapy with estrogen/progesterone in postmenopausal women can dramatically improve bone mineral density (BMD) and reduce fracture risk; however, there are little data on the effect of hormone replacement in young women with POF. At present, young women with POF are given either combined hormone replacement treatment or physiologic SSR (pSSR) consisting of combined transdermal estradiol and vaginal progesterone replacement regimens.This open-label, randomized controlled crossover pilot trial was designed to determine whether a regimen of pSSR could improve skeletal health among young women with POF caused by a variety of reasons. A total of 34 patients were randomized to receive a 4-week cycle of either pSSR (transdermal estradiol 100 mu g daily for week 1 and 150 mu g for weeks 2-4, with progesterone 200 mg twice daily for weeks 3-4) or standard hormone replacement therapy (sHRT) (oral ethinyl estradiol 30 mu g and norethisterone 1.5 mg daily for weeks 1-3, followed by 7 "pill-free" days for 12 months). Dual-energy x-ray absorptiometry was used to measure BMD at baseline and after each 12-month treatment period. During the study period, blood samples were collected for hormonal measurements and for markers of bone formation (bone alkaline phosphatase and procollagen type I amino-terminal propeptide) and bone resorption (CrossLaps [ cross-linked C-terminal telopeptide of type I collagen]) before and after each washout period, and at 3, 6, and 12 months. Of the 34 women, 18 (mean age 27; range, 19-39 years) completed the study. LH (luteinizing hormone) and FSH (follicle-stimulating hormone) were decreased to a similar extent by both pSSR and sHRT. Treatment with pSSR increased the mean baseline lumbar spine BMD z-score by +0.17 (95% confidence interval: +0.07 to +0.27; P = 0.003), whereas there was no significant increase in response to sHRT (+0.07, with a 95% confidence interval: -0.03 to +0.18; P = 0.2). During pSSR, the increment in lumbar spine BMD z-score was positively associated with estradiol (r = +0.49; P = 0.04) and inversely associated with FSH (r = -0.65; P = 0.004). Both bone alkaline phosphatase and procollagen type I amino-terminal propeptide were increased significantly by pSSR ((ANOVA) P < 0.001). In contrast, both of these bone formation markers were decreased by sHRT (P < 0.01). The bone resorption marker, CrossLaps, was suppressed by both regimens (P < 0.001).These findings demonstrate that pSSR, but not sHRT, over a 12-month period is associated with a significant improvement in parameters of bone health among women with POF.