Initiating Transdermal Estradiol Therapy in Turner's Syndrome

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.