title: Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement.
abstract: BACKGROUND
  Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD).
  
  
  OBJECTIVE
  The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women.
  
  
  METHODS
  This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland).
  
  
  METHODS
  Young women with primary ovarian insufficiency participated in the study.
  
  
  METHODS
  We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 μg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 μg/d) or placebo.
  
  
  METHODS
  Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry.
  
  
  RESULTS
  At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well.
  
  
  CONCLUSIONS
  Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.
authors.affiliation: Intramural Research Program in Reproductive and Adult Endocrinology (V.B.P., S.N.K., V.H.V., L.M.N.) and Program in Developmental Endocrinology and Genetics (K.A.C.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Biostatistics and Clinical Epidemiology Service (D.K.) and Division of Nuclear Medicine (J.C.R.), Warren G. Magnuson Clinical Center, Bethesda, Maryland 20892; and Office of Biostatistics Research (J.F.T.), Division of Cardiovascular Sciences, National Heart Lung and Blood Institute, Bethesda, Maryland 20892.
authors.forename: Vaishali B
authors.initials: VB
authors.lastname: Popat
authors.forename: Karim A
authors.initials: KA
authors.lastname: Calis
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Kalantaridou
authors.forename: Vien H
authors.initials: VH
authors.lastname: Vanderhoof
authors.forename: Deloris
authors.initials: D
authors.lastname: Koziol
authors.forename: James F
authors.initials: JF
authors.lastname: Troendle
authors.forename: James C
authors.initials: JC
authors.lastname: Reynolds
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nelson
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000188:drug therapy / Q000378:metabolism; D015502:Absorptiometry, Photon; D000279:Administration, Cutaneous; D000328:Adult; D015519:Bone Density / Q000187:drug effects*; D003271:Contraceptive Agents, Female / Q000008:administration & dosage; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000378:metabolism; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D016649:Primary Ovarian Insufficiency / Q000188:drug therapy* / Q000378:metabolism*; D011446:Prospective Studies; D013739:Testosterone / Q000008:administration & dosage* / Q000097:blood; D013812:Therapeutics; D055815:Young Adult
chemical_list: D003271:Contraceptive Agents, Female; D013739:Testosterone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate