Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial.
BACKGROUND
The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined.


OBJECTIVE
The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years.


METHODS
This study was a prospective, randomized, double-blind, placebo-controlled clinical trial.


METHODS
The study was conducted at two US pediatric endocrine centers.


METHODS
Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset.


METHODS
Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age.


METHODS
The main outcome measures for this report were median ages at Tanner breast stage ≥2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed.


RESULTS
Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not.


CONCLUSIONS
In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome.
Indiana University School of Medicine (C.A.Q.), Indianapolis, Indiana 46202; Novartis Pharmaceuticals (X.W.), East Hanover, New Jersey 07936; GCE Solutions Inc (S.G.), Bloomington, Illinois 61701; Thomas Jefferson University (K.K.), Philadelphia, Pennsylvania 19107; Gordon Cutler Consultancy, LLC (G.B.C.), Deltaville, Virginia 23043; and Thomas Jefferson University (J.L.R.), Philadelphia, Pennsylvania 19107.
Charmian A
CA
Quigley
Xiaohai
X
Wan
Sipi
S
Garg
Karen
K
Kowal
Gordon B
GB
Cutler
Judith L
JL
Ross
D000293:Adolescent; D001827:Body Height / Q000187:drug effects; D001940:Breast / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004967:Estrogens / Q000008:administration & dosage; D004997:Ethinyl Estradiol / Q000008:administration & dosage*; D005260:Female; D006062:Gonadotropins / Q000097:blood / Q000378:metabolism; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008572:Menarche / Q000187:drug effects*; D010919:Placebos; D011627:Puberty / Q000187:drug effects*; D016896:Treatment Outcome; D014424:Turner Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D055815:Young Adult
D004967:Estrogens; D006062:Gonadotropins; D010919:Placebos; D004997:Ethinyl Estradiol