Initiating Transdermal Estradiol Therapy in Turner's Syndrome
Initiating Transdermal Estradiol Therapy in Turner's Syndrome
This is a multicenter, randomized, controlled, semi-blinded study to compare two low doses of
 estradiol administered by recently available transdermal patches for the initiation of
 puberty in Turner syndrome girls 11.5-13.0 years old in conjunction with growth hormone (GH)
 therapy.

 The specific hypotheses to be tested are: when combined with growth hormone (GH) treatment,
 low dose transdermal estradiol (LTE2) replacement will be more effective in stimulating
 feminization, height velocity, and bone mineral density without compromising growth potential
 than very low dose transdermal estradiol (VLTE2), which will in turn be superior to GH alone
 in effects on feminization, height velocity, and bone mineral density.
Determining the estrogen replacement regimen which is optimal with GH therapy is an important
 issue in the management of Turner syndrome today. The estrogen effect on growth is biphasic,
 stimulatory at low doses but inhibitory at higher doses (1). In addition, the form, route,
 and timing of estrogen seem to be important determinants of estrogen effects on growth (2).
 Pubertal estrogen replacement treatment is customarily delayed until about 15 years of age in
 the USA to give GH treatment more time to act because standard estrogen treatment inhibits
 growth (3), in part by direct effects on epiphyseal senescence and fusion (4, 5) and in part
 by acting as a GH antagonist (6).

 Our pilot studies suggest that the form and route of estrogen are important determinants of
 estrogen effects on growth (2, 7). We recently found that very low doses of parenteral (IM
 depot) estradiol (E2) together with recombinant growth hormone (GH) to Turner syndrome
 patients as young as 12-12.9 years of age produced a significantly greater adult height than
 standard doses of oral conjugated estrogen at this age (7). Thus, very low doses of the
 natural estrogen (estradiol, E2) administered into the systemic circulation seem optimal for
 growth stimulation.

 Very little data are available about the optimal E2 dose for stimulation of epiphyseal growth
 and how this may relate to the optimal dosage for accrual of bone mineral density and
 feminization.

 Our recent pilot study started with a depot E2 dose of 0.2 mg; the monthly dose was then
 increased by 0.2 mg at successive 6-month intervals. The lowest dose (0.2 mg) stimulated
 height velocity the most. However, it did not stimulate breast development as reliably as the
 larger doses (≥ 0.4 mg monthly), which were also growth stimulatory although to a lesser
 extent. We propose to resolve questions about whether these disparities were due to the
 invariable sequential administration of successively larger doses or the inaccuracy of
 delivery of such low doses by injection, and also to compare the effects on bone mineral
 density of the equivalent very low and low doses of E2 delivered by transdermal patch.
 Transdermal E2 delivery systems are now available for easily and reliably delivering the
 comparable very low doses of E2 in a form more suitable for routine patient care. The current
 guidelines recommend starting an E2 starting dose for the induction of puberty (5-12.5 mcg
 daily) that is about one-tenth to one-eighth of the adult dose (100 mcg daily) (8). However,
 these guidelines note that it is not established whether various means of patch dose
 fractionation (e.g., administering a quarter patch overnight or daily or administering whole
 patches for 7-10 days per month) are equivalent.

 Pharmacokinetic study of transdermal E2 in Turner syndrome teens showed absorption of E2 by
 first order kinetics (9). Steady state was achieved approximately 9 hrs after application of
 a 37.5 µg patch, and serum concentrations reached a mean of 52.9 ± 17.8 (SD) pg/ml. This
 demonstrates a rise in plasma estradiol of about 1 pg/ml (3.67 pmol/l) for every 1.0 µg
 applied to the skin, similar to package insert data in adults. This would suggest that a
 starting dose of 5-10 ug transdermal E2 daily approximates the 133-266 µg monthly amount of
 E2 delivered by the 0.2-0.4 mg monthly injections of E2 cypionate.

 Our preliminary data support this extrapolation. In n = 3 Turner syndrome patients combining
 a transdermal E2 dose of 17.8 ± 2.1 (SD) mcg for an average of 14 days a month with GH
 therapy for 1.0 year showed increases in breast tissue diameter of 1.8 ± 0.3 cm (i.e., breast
 budding), bone mineral density of 0.067 ± 0.06 gm/cm2 in the lumbar spine, and height
 velocity of 5.16 ± 1.37 cm/year. The new VLTE2 (14 mcg) patch increases lumbar spine bone
 mineral density 2.4% at 1 year in post-menopausal women (P <0.001), but no trials have been
 conducted in children (package insert).

 We now propose to move beyond proof of the principle that systemic administration of very low
 or low dose E2 is efficacious to the practical application of E2 treatment. Our study used IM
 depot E2 (E2 cyclopentylpropionate, which is two-thirds E2), the very low doses of which
 required a compounding pharmacy to prepare a stock solution of 1.0 mg/cc. This was helpful
 with compliance, but not necessarily accurate and certainly not convenient for routine
 dispensing of prescriptions. Practically, we propose to extrapolate from this experience with
 parenteral to the readily available and highly acceptable transdermal preparations: the 14
 mcg patch worn for 10 days a month delivers an E2 profile approximately equivalent to the 0.2
 mg monthly dose of depot E2, and a 25 mcg patch worn for 10 days a month is approximately
 equivalent to the 0.4 mg monthly dose of depot E2 (7).
Inclusion Criteria:

 -  60 subjects will be recruited from participating Pediatric Endocrinology Clinics in
 the United States.

 -  Subjects will be 11.5-13.0 years of age and must have completed at least 6 months of
 GH therapy prior to the study.

 -  Subjects may not have had any estrogen prior to the study. All subjects must be breast
 stage 1 and euthyroid prior to the study

 -  Those on thyroid medication will continue the appropriate thyroid replacement therapy
 during the study.

 Exclusion Criteria:

 -  On estrogen therapy, breast stage 2 or greater, not on GH for at least 6 months.