Effect of transdermal vs.oral estrogen therapy on achieving near final adult height and near peak bo

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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 syndrome
Sevket Yigit M.D
Connecticut Childrens Medical Center Endocrinolog
y and Diabetes
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ABSTRACT

• 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.

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GONADAL DYSGENESIS CHRONIC ESTROGEN DEFICIENCY
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Background

• 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.

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• TYPES OF ESTROGEN TREATMENT
• Oral vs. transdermal ( systemic)
• Oral estrogen first pass effect through the
  liver
• Transdermalprovides constant serum levels
  similar to ovarian estradiol secretion

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Hypotheses

• 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 adolescents.

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Preliminary Studies

• 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 estrogen.
• 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 estrogen(1).

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• 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).

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• 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 therapy(6) .
• 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).

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• 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
  both.

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Specific Aims

• 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

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Inclusion criteria

• 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

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Exclusion Criteria

• 1. Underlying chronic disease or use of
  medications known to
• interfere with bone metabolism ( ie.
  anticonvulsants,
• glucocorticoids)
• 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.
• 6. Pregnancy

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Selectively randomized prospective study
Group 2 Turner Syndrome (12-15 years
old)
Group 1 Turner Syndrome ( 12-15 years old)
Bone Age Matched
Sample size 12 for each group
INITIAL EVALUATION
INITIAL EVALUATION
TRANSDERMAL ESTRADIOL
ORAL ESTRADIOL
0.0125 mg for 6 months 0.025 mg for 6
months 0.0375 mg for 6 months 0.05 mg for 6
months
0.25 mg for 6 months 0.5 mg for 6 months 0.75
mg for 6 months 1 mg for 6 months
Evaluations every 6 months
FINAL EVALUATION
FINAL EVALUATION
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Outcome Measures

• Height,height velocity
• Bone age
• Growth factors (IGF-1, IGFBP-3)
• Bone turnover markers (BS-ALP, osteocalcin, PINP,
  N-telopeptides)
• Bone mineral density ( yearly)
• Pubertal hormones (estradiol, estrone, SHBG, LH,
  FSH, total and free testosterone, DHT, DHEA-S).

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Significance

• 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 .

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WORK IN PROGRESS

• Grant supports GCRC University of Connecticut,
  Endocrine Fellows Foundation, Eli-Lilly Company
• Recruitment of subjects is in progress currently.
• There is no preliminary data available.

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References

• 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.200085(1) 464-467
• 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 199851(2) 147-158
• 6)Lanes R Decreased bone mass despite long term
  estrogen replacement therapy in young women with
  Turners 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)