A 15-year-old girl with Turner syndrome presented to our hospital with a
dilemma: She was on growth hormone and needed to start estrogen replacement.
The patient was refusing my prescription for conjugated estrogens
tablets (Premarin, Wyeth Pharmaceuticals).
I know I need to start estrogen, but it wont be horse
estrogen, not Premarin, no way! You know I am a vegetarian, I love animals and
Ive been on the Internet. There are other estrogens that dont come
from animals and thats what I want, she said.
This experience prompted me to explore all of the alternative
Estrogen is one of the most commonly prescribed drugs used by both
menopausal woman and young women with premature ovarian failure. Estrogen
replacement therapy is prescribed to replace the three principal forms of
estrogen found in the human female body: estrone, estradiol and estriol. From
menarche to menopause, estradiol is the primary estrogen responsible for
inducing puberty and maintaining feminization. In 1942, Wyeth produced the
first FDA-approved estrogen replacement therapy; namely, Premarin, which is
isolated from PREgnant MARes urINe (PMU) and is a mixture of conjugated
For more than 50 years Premarin has been the most commonly prescribed
estrogen supplement in the United States. However, the demand for alternative
forms of estrogen replacement is growing.
Major concern about Premarin was prompted by the 2002 reports of adverse
events from the Womens Health Initiative. Results of this randomized
controlled trial showed an increased risk of stroke, breast cancer and
cardiovascular disease in older women assigned the drug. Investigators wondered
if these adverse events would have been observed with all forms of estrogen or
whether they might have been specific to the oral conjugated equine estrogen.
In addition, resistance to the use of Premarin has increased in response to the
reports concerning the treatment of the pregnant mares, their foals, and the
methods used to collect their urine for the production of oral conjugated
equine estrogen. For these reasons, some patients and practitioners may seek
alternatives to oral conjugated equine estrogen for estrogen replacement
There are several FDA-approved hormone preparations that are identical
in structure to human estrogens produced normally. Lack of familiarity with
these formulations and potency has hampered physicians from prescribing them.
Before deciding on the type of estrogen replacement to prescribe for a
patient like the one described above, I had to review the source, dosages, and
the route of alternative estrogen preparations as well as additional
medications she was currently taking. I shared this information with the
patient to allow her to make an informed choice. This discussion served not
only to increase the likelihood she would comply but also educated her about
potential adverse effect. (see table 1 for a comparison of the different
estrogen formulations). The patient preferred to take estradiol, a product
derived from yams. Estradiol is identical to the hormone produced by the human
body. It is a brand name product that is FDA-approved, has been well tested and
comes in a conveniently standard dosage (see table 2).
Table 1: FDAApproved Estrogen
Source: Equipotent dosing:
Handbook of Clinical Drug Data, 10th Edition McGraw-Hill 2002.
|Conjugated Estrogens Source = pregnant horse urine
(Premarin, Wyeth Pharmaceuticals)
||Esterified Estrogens Source = Yams (Estratab, Solvay
Pharmaceuticals Inc.; Menest, King Pharmaceuticals Inc.)
||Estradiol Source = Soy/Yams (Estrace, Bristol-Myers
Squibb; Vivelle and Estraderm, Novartis Pharmaceuticals; Climara, Berlex
|Sodium estrone sulfate
||Sodium estrone sulfate
||17-beta Estradiol (E2)
|Sodium equilin sulfate
||Sodium equilin sulfate
|Sodium sulfate conjugates
The next decision related to what route of the hormone she would take.
The patient was on GH therapy and some research involving oral estrogen in any
form in girls with Turner syndrome has shown that it interferes with the
positive effects of GH therapy. Most of these studies have been done with oral
estrogen. Oral conjugated equine estrogen and oral beta estradiol have been
associated with decreases in levels of IGF-1 of up to 30%, which may
potentially reduce the benefits of GH; however, transdermal estradiol has not.
This is thought to be due to first pass metabolism of oral estrogens in the
Like all females with hypogonadism, the patient is at increased risk of
CVD. In patients with Turner syndrome, ischemic heart disease has been reported
to be twice as common as in the general population. Since oral estrogen therapy
has been linked to increased CV risk, this might not be the best route of
Table 2: Estrogen Equivalencies
|Conjugated estrogen (Premarin, Wyeth Pharmaceuticals)
||Tablet: 0.3, 0.625, 0.9, 1.25, 2.5 mg
|Urine of pregnant mares
|Esterified Estrogen (Estratab, Solvay Pharmaceuticals Inc.;
Menest, King Pharmaceuticals Inc.)
||Tablet: 0.3, 0.625, 1.25, 2.5 mg
|Estradiol 17 beta (Estrace, Bristol-Myers Squibb)
||Tablet: 0.5, 1, 1.5, 2 mg
|Estradiol 17 patch (Vivelle, Estraderm, Novartis
Pharmaceuticals; Climara, Berlex Laboratories)
||Transdermal Patch: 25, 37.5, 50, 75, 100
After consumption of oral estrogen, the hormone is initially metabolized
through the liver. This process may stimulate an increase in biochemical
factors linked to inflammation. Elevations of C-reactive protein have been
observed with oral estrogens in older women. Long-term use of oral estrogen
replacement therapy has been shown to be associated with elevated levels of CRP
even in apparently healthy women. Preliminary studies using transdermal 17-beta
estradiol have not duplicated these findings, possibly because it is not first
metabolized through the liver.
Transdermal estrogen offers other advantages over oral formulations.
Some patients find it easier to comply with wearing a patch rather than
swallowing a pill. Several experts in the treatment of Turner syndrome
recommend transdermal estrogen formulation for their patients. Todays
science and technology has advanced hormone replacement therapy to the state of
the art in which providers can prescribe medications that are molecularly
identical to that produced by the human body. This technology has been used to
make thyroxin and insulin rather than rely upon older methods of hormones
extracted from beef and pork. It may now be the time to move away from equine
sources of estrogen as well.
The optimal dose and route of estrogens remain controversial because of
a lack of head-to-head comparison studies. Researchers at Stanford and
elsewhere are conducting ongoing research to compare varying oral and
transdermal estrogen therapies in adolescents with ovarian failure. We hope the
results will provide some needed answers for our patients.
Eileen Durham, C-PNP, MSN, RN, is with the Division of Pediatric
Endocrinology and Diabetes at Lucile Packard Childrens Hospital at
Stanford, Palo Alto, Calif.
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