Effect of transdermal vs.oral
estrogen therapy on achieving near
final adult height and near peak
bone mass in growth hormone
treated adolescents with Turner
Sevket Yigit M.D
Connecticut Children’s Medical Center
Endocrinology and Diabetes
Estrogen replacement in Turner Syndrome (TS) is accomplished most commonly
using oral estrogen preparations. Based on preliminary data we hypothesize that
transdermal vs oral estradiol will have more favorable effect on near final adult
height (FAH) and near peak bone mass (PBM) in growth hormone (GH) treated
adolescents with TS. The aim of the study is to evaluate the effect of transdermal vs.
oral estrogen on growth and bone mass and their correlation with growth factor
levels, markers of bone turnover and sex steroid levels. This 2 year selectively
randomized prospective study involves two treatment groups: equivalent doses of
oral vs. transdermal estradiol in combination with standard growth hormone
therapy. The TS adolescents ages 12-15 years will be selectively randomized to
each group by bone age. Estrogen dose will be gradually increased every 6 months
over the two years in both groups mimicking normal puberty. With a sample size of
12 in each group and test significance level of 0.05, we will have 80 % power to
detect a 25 % difference in growth of two groups. There is no preliminary data in
terms of bone mass to evaluate sample size estimation for significant difference
between two groups. Analysis of outcomes will be done between study groups as
well as within each study group over time.
CHRONIC ESTROGEN DEFICIENCY
•Individuals with Turner Syndrome (TS) are estrogen deficient
during their pubertal and postpubertal years. Estrogen therapy is
needed during adolescence not only to provide adequate
feminization but may play a role in maximizing near final adult
height (FAH) and near peak bone mass (PBM) if administered more
physiologically in combination with growth hormone (GH) therapy.
•ESTROGEN THERAPY IN TS
•Low dose stimulates linear growth.
•High dose inhibits growth.
•Ideally it has to augment growth, should not prematurely induce
epiphysial fusion and should enhance FAH and PBM.
•Estrogen therapy in TS should mimic normal puberty.
• TYPES OF ESTROGEN TREATMENT:
• Oral vs. transdermal ( systemic)
• Oral estrogen… first pass effect through the liver
• Transdermal…provides constant serum levels similar to
ovarian estradiol secretion
•Transdermal versus oral estradiol will have a
more favorable effect on linear growth and
near FAH in GH treated TS adolescents.
•Transdermal versus oral estradiol will also
have a more favorable effect on bone mass
accrual and near PBM in GH treated TS
• A number of investigators have studied the interplay
between exogenous estrogen and the GH- IGF-1 axis in
adult females. Hypogonadal women with transdermal
estradiol require lower doses of GH than those on oral
• Roelfsena observed that a switch from equivalent doses of
oral to transdermal estradiol increased IGF-1 levels
significantly in 20 adult women with LH and GH
deficiency suggesting increased effectiveness of GH
therapy when receiving transdermal as compared to oral
• Ho reports increased GH but decreased IGF-1 levels in
oral estrogen treated postmenopausal women presumed to
result from the direct inhibitory effect of high estradiol
concentration on hepatic IGF-1 production. In a
subsequent study, Ho observed enhanced IGF-1 production
and evidence of increased osteoblastic bone formation in
transdermal estrogen treated postmenopausal women (2,3).
• Rosenfield studied the effect on growth of systemic
estrogen as compared to oral estrogen in combination with
GH therapy. They compared I.M. depot estradiol initiated
at low doses and increased gradually every 6 months over
2 years with routine oral estrogen therapy. Gain in near
FAH at 2 years was 2.6 cm greater in depot estradiol vs
routine estradiol group ( p< .001)(4).
• Recent epidemiological studies in Denmark reported a
significantly increased prevalence of symptomatic
osteoporosis with fractures at all ages in TS but which
increases substantially during later adulthood(5). Lanes
studied young TS women (mean age 18.2 years) with
previously normal bone density at the time GH therapy
was discontinued and observed decreased bone mass
several years later despite continuous oral estrogen
• At our institution, Onyirimba and Rubin compared the
effect of transdermal vs. oral estrogen therapy in 15 TS
young adults ( mean age 21.6 years) on bone turnover and
its correlation with growth factors and gonadal steroid
levels. They observed a relative preservation of IGF-1 and
a significant decrease in IGFBP-3 in the transdermal as
compared to oral estradiol group which was associated
with a net increase in markers of bone formation (7).
• Collectively, the preliminary data supports the
use of low dose systemic estradiol for initiation
of estrogen therapy in GH treated TS young
adolescents with gradual increments over a
several year period. This more physiological
treatment approach has greater potential to
promote both FAH and PBM in a group of
individuals with limited genetic potential for
• To measure increments in growth and near FAH in GH
treated TS adolescents on transdermal vs oral estradiol.
• To measure increments in bone mineral density and near
PBM in a group of GH treated TS adolescents on
transdermal vs oral estradiol.
• To correlate the changes in growth and bone mineral
density with changes in growth factor levels, markers of
bone turnover, and pubertal hormones
1. TS girls ages 12 to15 years.
2. On standard GH treatment for 2 years or more
3. No previous estrogen therapy or on low dose estrogen
therapy for less than or equal to one year with a wash-out period of
three months prior to study entry.
4. TS girls with adequately treated hypothyroidism
1. Underlying chronic disease or use of medications known to
interfere with bone metabolism ( ie. anticonvulsants,
2. Patients with major contraindications for estrogen therapy
(Patients with hypercoagulability, and severe liver disease by
history are excluded)
3. History of fracture or immobilization in the last one year.
4. Mosaic TS patients with spontaneous puberty.
5. Mosaic TS patients with sufficient estradiol levels.
Selectively randomized prospective study
Group 1 Group 2
Turner Syndrome Bone Age Matched Turner Syndrome
( 12-15 years old) (12-15 years old)
Sample size: INITIAL EVALUATION
12 for each group
TRANSDERMAL ESTRADIOL ORAL ESTRADIOL
0.0125 mg for 6 months 0.25 mg for 6 months
0.025 mg for 6 months 0.5 mg for 6 months
0.0375 mg for 6 months every 6 months 0.75 mg for 6 months
0.05 mg for 6 months 1 mg for 6 months
FINAL EVALUATION FINAL EVALUATION
• Height,height velocity
• Bone age
• Growth factors (IGF-1, IGFBP-3)
• Bone turnover markers (BS-ALP, osteocalcin,
• Bone mineral density ( yearly)
• Pubertal hormones (estradiol, estrone, SHBG,
LH, FSH, total and free testosterone, DHT,
– Recent observations suggest possible advantages of systemic vs.
oral estrogen therapy on FAH and PBM in TS. Considering the
fact that on average, 15% of FAH and 40% of PBM are achieved
during puberty, adolescents with TS may benefit from
transdermal vs oral estrogen therapy with regard to FAH and
PBM. Since a relatively small increment in bone mass can result
in a significant decrease in fracture risk later on, use of
transdermal vs oral estrogen may decrease the risk of developing
symptomatic osteoporosis in TS. Long term transdermal estrogen
therapy may result in long term benefits in this population .
WORK IN PROGRESS
• Grant supports: GCRC University of
Connecticut, Endocrine Fellows Foundation,
• Recruitment of subjects is in progress currently.
• There is no preliminary data available.
• 1)Roelfsema , F , Janssen Y., A switch from oral (2mg/day) to transdermal ( 50
mcg/day) 17-beta estradiol therapy increases serum IGF-1 levels in recombinant GH
substituted women with GH deficiency. J. of Clin.Endoc.and Metab.2000;85(1): 464-
• 2)Ho K.Y, Lazarus L., Contrasting effects of oral and transdermal routes of estrogen
replacement therapy on 24 hour growth hormone (GH) secretion, IGF-1 and GH binding
protein in ostmenopausal women. J. of Clin.Endoc. and Metab.1991; 72 (2): 374-381
• 3)Ho K.Y, Weissberger A.J , Impact of short term estrogen administration on growth
hormone secretion and action: Distinct route dependent effects on connective tissue and
bone tissue metabolism. J. of Bone and Mineral Research.1992; 7(7):821-827
• 4)Rosenfield R. Optimizing estrogen replacement treatment in Turner Syndrome.
Pediatrics 1998; 102: 486-488
• 5)Gravholt CH. Morbidity in Turner Syndrome. J. Clin. Epidemiol 1998;51(2): 147-158
• 6)Lanes R Decreased bone mass despite long term estrogen replacement therapy in
young women with Turner’s Syndrome and previously normal bone density. Fertil.
Steril-1999 Nov; 72(5)-896
• 7)Onyirimba M, Rubin K. Effect of Transdermal vs. Oral estradiol on growth factors
and markers of bone turnover in young adults with TS.( Manuscript in preparation)