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Misconception and Concerns About Bioidentical Hormones Used For Custom-Compounded Hormone Therapy
Misconception and Concerns About Bioidentical Hormones Used For Custom-Compounded Hormone Therapy
C o m m e n t a r y
he results of the Women’s Health Initiative hormone The objectives of the present commentary are: 1) to
T therapy (HT) trials have caused both apprehension
and confusion about the overall risks and benefits asso-
show that the so-called “bioidentical” hormones in cus-
tom-compounded HT preparations may not be identical
ciated with postmenopausal HT (1). Since the results were to those made in the body; and 2) to point out how the lack
published, patient and clinician interest in potential alter- of regulation of these hormone products can cause adverse
natives to conventional HT has grown immensely and effects in postmenopausal women using them.
continues to grow. This appears to be particularly true for
products or regimens that claim to have fewer risks and Classification of Steroids Used for
side effects than commercially available HT preparations. Postmenopausal HT
One commonly used alternative HT involves custom-
compounded hormone preparations. The hormones in these For simplicity and to document potential pharmacological
preparations include estrogen [17-estradiol (estradiol), es- differences, various steroid hormones used for HT can be
divided into four groups: 1) natural (class A); 2) native to
trone, and/or estriol], progesterone, testosterone, andro-
the body and synthesized from natural precursors (class
stenedione, and dehydroepiandrosterone. The products can
B); 3) native to the body and synthesized from nonsteroi-
be prepared in individualized dosages and forms such as
dal precursors (class C); and 4) synthetic and not native to
creams, gels, lotions, sublingual tablets, troches (lozenges)
the body (class D).
for buccal administration, and suppositories by compound-
ing pharmacies from a clinician’s prescription. They are Class A steroids
often touted by advocates as safer than commercially pre- The steroids in class A are found in nature and are
pared HT products. Proponents also claim that custom- formulated into drugs without undergoing any chemi-
compounded HT is associated with fewer side effects and cal modifications. For example, conjugated equine es-
may provide better symptom relief than conventional HT trogens are estrogens in the form of sulfate esters, which
because the hormones used in the preparations are are simply extracted from pregnant mare’s urine and do
“bioidentical,” i.e. identical to those made in the body. not undergo chemical modification. Approximately
The majority of these claims are unsubstantiated, and 50% of conjugated equine estrogens consist of estrone
sulfate, and the remaining approximate 50% consists of
no rigorous randomized control trials have been carried
equine estrogens. Equine estrogens are native to the
out to support any of the claims. Because the custom-
horse but not the human.
compounding of HT products is not regulated, a par-
ticular concern is that some women may be overdosed, Class B steroids
or treated with ineffective products, or subject to un- The class B steroids are semisynthetic. They are steroids
identified risk. that exist in nature and are biosynthesized by the human
ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviation: HT, Hormone therapy.
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2011-2492 Received September 6, 2011. Accepted December 6, 2011.
First Published Online December 28, 2011
body, but for these to be formulated as therapeutic agents, ficult to differentiate between class B and class C steroids.
they need to be chemically synthesized from a natural However, there can be significant differences in both the
starting material, most commonly from a plant source chemical and biological properties of the steroids made by
such as the Mexican yam and soybean. These plants con- these two distinct methods.
tain sterols such as diosgenin and stigmasterol, which are In total synthesis, there is one fundamental requirement
used as precursors for the synthesis of a variety of steroids. and, that is, the steroid synthesized has to have the same
Essentially, steroid hormones such as estradiol, estrone, precise stereochemistry as that of the naturally occurring
estriol, progesterone, dehydroepiandrosterone, andro- hormone. It is only then that the synthesized hormone will
stenedione, testosterone, cortisol, aldosterone, synthetic have the same biological activity. It is obligatory that the
conjugated estrogens, etc., have been chemically synthe- very specific three-dimensional structure be the same for a
sized from these sources for decades. Contrary to many
the availability of resources for standard inspections and erature, or information that is not evidence-based. In most
enforcement. instances, serum levels achieved by a particular custom-
A major concern about the custom-compounded prod- prepared hormonal preparation are not determined by the
ucts is that the practice of drug compounding is not subject physician. In addition, custom-compounded hormonal
to the same degree of regulations and oversight by the FDA preparations can be purchased and used by women with
and by regulatory authorities in other countries, which is no oversight by physicians as to the medical history of the
required for the commercial production and marketing of
patient, potential presence of risk factors, or the serum
prescription medicines. Unlike commercially available
levels of active hormones attained with these products.
drugs, compounded medicines are not tested routinely by
After becoming aware of product quality control prob-
any regulatory agency for quality, purity and potency. In
lems associated with custom-compounded hormone prep-
addition, there are no product labeling requirements for
the custom formulations. This differs from commercially arations, the FDA’s Division of Prescription Drug Com-
available drugs, which are required to be sold with a pack- pliance and Surveillance examined 29 compounded drugs
age insert that details the product’s indications for use, obtained from 12 compounding pharmacies (8). The
contraindications, pharmacokinetics, and adverse events, agency reported that 10 of the products (34%) failed one
using language approved by regulatory authorities. or more of their standard quality tests, including nine
products (one of which was progesterone) that failed be-
cause they contained less of the active ingredient than in-
Concerns about Accuracy of Hormone dicated on the label.
Doses in Custom-Compounded Hormonal Potential underdosing with progesterone has been re-
Preparations ported in three women who developed endometrial cancer
after using custom-compounded HT to relieve meno-
Because there is no strict regulation and oversight of com-
pausal symptoms (9). The HT preparations included tro-
pounded medicines, postmenopausal women using cus-
tom-prepared hormonal preparations may be subject to ches containing varying doses of estrone, estradiol, estriol,
underdosing or overdosing of the products. Steroid doses progesterone, and dehydroepiandrosterone, and were
of products prepared by custom-compounding pharma- used for 2– 4 yr. The final diagnosis of these subjects was
cies are not regulated, and most often little is known about stage 1A or 1B, grade 2, endometrial cancer. The authors
the pharmacokinetics of the products. The doses can be of the report raised the possibility that the estrogenic com-
based on a physician’s prescription, report(s) from the lit- ponent of the troche was significantly absorbed but the
J Clin Endocrinol Metab, March 2012, 97(3):756 –759 jcem.endojournals.org 759
progesterone dose was inadequate, thereby causing endo- the misleading term “bioidentical hormone” is inappro-
metrial hyperplasia. priate, and its use should be discouraged.
Although hormones in custom-compounded HT have
risks similar to those in regulatory-approved products, e.g.
increased risk of a blood clot, heart attack, stroke, breast Acknowledgments
cancer, gall bladder disease, etc., there is even a higher risk
if the hormone dose in a product is greater than expected. Address all correspondence and requests for reprints to: Frank Z.
In one study, healthy postmenopausal women were Stanczyk, Ph.D., Professor of Research, Departments of Obstet-
rics and Gynecology, and Preventive Medicine, University of
treated for 2 wk with a custom-compounded testosterone
Southern California, Keck School of Medicine, Livingston Re-
preparation, either a gel containing 1 mg of testosterone or
search Building, 1321 North Mission Road, Room 201, Los
a lozenge containing 1 mg of testosterone propionate (10).