The Bioidentical Hormone Debate: Are Bioidentical Hormones (Estradiol, Estriol, and Progesterone) Safer or More Efficacious than Commonly Used Synthetic Versions in Hormone Replacement Therapy?

Abstract

The use of bioidentical hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their relative safety compared with traditional synthetic and animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic progestins. Proponents for bioidentical hormones claim that they are safer than comparable synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration and The Endocrine Society, there is little or no evidence to support claims that bioidentical hormones are safer or more effective.
This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease.
Published papers were identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in vitro results, were selected.
Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone.
Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.

Full text

Postgraduate Medicine: Volume 121: No.1
The Bioidentical Hormone Debate:
Are Bioidentical Hormones (Estradiol, Estriol, and Progesterone) Safer or More Efficacious than
Commonly Used Synthetic Versions in Hormone Replacement Therapy?
Kent Holtorf, MD
Abstract:
Background: The use of bioidentical hormones, including progesterone, estradiol, and estriol, in
hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their
relative safety compared with traditional synthetic and animal-derived versions, such as
conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic
progestins. Proponents for bioidentical hormones claim that they are safer than comparable
synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration
and The Endocrine Society, there is little or no evidence to support claims that bioidentical
hormones are safer or more effective. Objective: This paper aimed to evaluate the evidence
comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the
commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast
tissue, and risks for breast cancer and cardiovascular disease. Methods: Published papers were
identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included
keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that
compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in
vitro results, were selected. Results: Patients report greater satisfaction with HRTs that contain
progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have
some distinctly different, potentially opposite, physiological effects compared with their synthetic
counterparts, which have different chemical structures. Both physiological and clinical data have
indicated that progesterone is associated with a diminished risk for breast cancer, compared with
the increased risk associated with synthetic progestins. Estriol has some unique physiological
effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry
less risk for breast cancer, although no randomized controlled trials have been documented.
Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with
progesterone. Conclusion: Physiological data and clinical outcomes demonstrate that
bioidentical hormones are associated with lower risks, including the risk of breast cancer and
cardiovascular disease, and are more efficacious than their synthetic and animalderived
counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred
method of HRT. Further randomized controlled trials are needed to delineate these differences
more clearly.
Introduction
The relative safety of bioidentical hormone replacement compared with traditional synthetic and
animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone
acetate (MPA), and other synthetic progestins is the subject of intense debate. According to The
Endocrine Society Position Statement, there is little or no evidence to support the claim that
bioidentical hormones are safer or more effective than the commonly used synthetic versions of
hormone replacement therapy (HRT).
1
Furthermore, the US Food and Drug Administration (FDA)
has ordered pharmacies to stop providing estriol, stating that it is a new, unapproved drug with
unknown safety and effectiveness.
Nevertheless, estriol has been used for decades without reported safety concerns and is a
component of medications approved for use worldwide. The FDA has acknowledged that it is
unaware of any adverse events associated with the use of compounded medications containing
estriol, and US Congress is considering a resolution (HR342) to reverse the FDA’s decision to
restrict its use. Claims by The Endocrine Society and the FDA are in direct contrast to those of
proponents of bioidentical hormones, who argue that these hormones are safer than comparable
synthetic versions of HRT. Such claims are not fully supported, which can be confusing for
patients and physicians.

One major reason for a lack of conclusive data is that, until recently, progestogens were lumped
together because of a commonly held belief that different forms of progestogens would have
identical physiological effects and risks, because they all mediate effects via the same
(progesterone) receptor. This view also applies to the different forms of estrogen, which are
commonly grouped together and referred to as estrogen replacement therapy.
The term “bioidentical HRT” refers to the use of hormones that are exact copies of endogenous
human hormones, including estriol, estradiol, and progesterone, as opposed to synthetic versions
with different chemical structures or nonhuman versions, such as CEE. Bioidentical hormones are
also often referred to as “natural hormones,” which can be confusing because bioidentical
hormones are synthesized, while some estrogens from a natural source, such as equine urine,
are not considered bioidentical because many of their components are foreign to the human
body.
This review will examine the differences between the bioidentical hormones estriol, estradiol, and
progesterone when used as components of HRT compared with synthetic or nonidentical
hormones such as CEE and synthetic progestins, including MPA. The article attempts to
determine whether there is any supporting evidence that bioidentical hormones are a potentially
safer or more effective form of HRT than the commonly used synthetic versions.
Methods
Definitions
Bioidentical hormones have a chemical structure identical to human hormones but are chemically
synthesized, such as progesterone, estriol, and estradiol. Nonbioidentical hormones are not
structurally identical to human hormones and may either be chemically synthesized, such as
MPA, or derived from a nonhuman source, such as CEE.
Databases and Keywords
Literature searches were conducted for HRT formularies, focusing on those that either are or
have been used in the United States. Published papers identified for review by
PubMed/MEDLINE, Google Scholar, and Cochrane database searches included the keywords:
“bioidentical hormones,” “synthetic hormones,” “progestin,” “menopausal hormone replacement,”
“hormone replacement therapy,” “HRT,” “estriol,” “progesterone,” “natural hormones,” “conjugated
equine estrogens,” “medroxyprogesterone acetate,” “breast cancer,” and “cardiovascular
disease.”
Comparisons
Published papers that focused on 3 key areas were identified: 1) clinical efficacy, 2) physiologic
actions on breast tissue, and 3) risks for breast cancer and cardiovascular disease. Papers
included human clinical studies that compared bioidentical and nonbioidentical hormones, animal
studies based on similar comparisons, and in vitro experimental work that focused on
physiological or biochemical aspects of the hormones.
Results
1) Symptomatic Efficacy of Synthetic Progestins versus Progesterone
Four studies of patients using HRT, including either progesterone or MPA, compared efficacy,
patient satisfaction, and quality of life. Women in all 4 studies reported greater satisfaction, fewer
side effects, and improved quality of life when they were switched from synthetic progestins to
progesterone replacement.
2-6
In a cross-sectional survey, Fitzpatrick et al compared patient
satisfaction and quality of life, as well as other somatic and psychological symptoms (ie, anxiety,
depression, sleep problems, menstrual bleeding, vasomotor symptoms, cognitive difficulties,
attraction, and sexual functioning) in 176 menopausal women on HRT with MPA versus HRT with
progesterone.
2
Significant differences were seen for all somatic, vasomotor, and psychological
symptoms, except for attraction, when bioidentical progesterone was used rather than MPA (P <
0.001).
The effect of progesterone compared with MPA included a 30% reduction in sleep problems, a
50% reduction in anxiety, a 60% reduction in depression, a 30% reduction in somatic symptoms,

a 25% reduction in menstrual bleeding, a 40% reduction in cognitive difficulties, and a 30%
improvement in sexual function. Overall, 65% of women felt that HRT combined with
progesterone was better than the HRT combined with MPA.
2
In a randomized study comparing HRT with MPA or progesterone in 23 postmenopausal women
with no mood disorders such as depression or anxiety, Cummings and Brizendine found
significantly more negative somatic effects but no differences in mood assessment with synthetic
hormones. These negative effects included increased vaginal bleeding (P = 0.003) and increased
breast tenderness (P = 0.02), with a trend for increased hot flashes with the use of MPA
compared with progesterone.
3
In the 3-year, double-blind, placebo-controlled Postmenopausal
Estrogen/Progestin Interventions (PEPI) trial, 875 menopausal women received either placebo,
CEE with MPA (cyclic or continuous), or progesterone (cyclic). Those taking progesterone had
fewer episodes of excessive bleeding than those on MPA (either continuous or cyclic),
4
but no
differences were noted in symptomatic relief.
5
2) Differing Physiological Effects of Bioidentical Progesterone and
Synthetic Progestins
Progesterone and synthetic progestins generally have indistinguishable effects on endometrial
tissue, which are not the focus of this review. Studies that compared the physiological differences
in breast tissue of those on progesterone, with those on other progestins, have the potential to
predict differing risks of breast cancer. While variations in methodology and study design are
considerable, most of the literature demonstrates physiological differences between progestins
and progesterone and their effects on breast tissue.
Synthetic progestins have potential antiapoptotic effects and may significantly increase estrogen-
stimulated breast cell mitotic activity and proliferation.
7-21
In contrast, progesterone inhibits
estrogen-stimulated breast epithelial cells.
16, 22-28
Progesterone also downregulates estrogen
receptor-1 (ER-1) in the breast,
27-29
induces breast cancer cell apoptosis,
30, 31
diminishes breast
cell mitotic activity,
7, 16, 22-24, 26-28, 31, 32
and arrests human breast cancer cells in the G1 phase by
upregulating cyclin-dependent kinase inhibitors and downregulating cyclin D1.
23, 32
Synthetic progestins, in contrast, upregulate cyclin D1
21
and increase breast cell proliferation.
7-21
Progesterone consistently demonstrates antiestrogenic activity in breast tissue.
7, 16, 22, 24-29, 31-34
This result is generally in contrast to that for synthetic progestins, especially the 19-
nortestosteronederived progestins, which bind to estrogen receptors in breast tissue (but not in
endometrial tissue) and display significant intrinsic estrogenic properties in breast but not
endometrial tissue.
11, 23, 35-39
Synthetic progestins may also increase the conversion of weaker endogenous estrogens into
more potent estrogens,
7, 40-45
potentially contributing to their carcinogenic effects, which are not
apparent with progesterone. Synthetic progestins may promote the formation of the genotoxic
estrogen metabolite 16-hydroxyestrone.
41
Synthetic progestins, especially MPA, stimulate the
conversion of inactive estrone sulfate into active estrone by stimulating sulfatase,
43, 44
as well as
increasing 17-beta-hydroxysteroid reductase activity,
7, 40, 42, 43, 45
which in turn increases the
intracellular formation of more potent estrogens and potentially increases breast cancer risk.
Progesterone has an opposite effect, stimulating the oxidative isoform of 17-beta-hydroxysteroid
dehydrogenase, which increases the intracellular conversion of potent estrogens to their less
potent counterparts.
34, 46, 47
At least 3 subclasses of progesterone receptors (PR) have been identified: PRA, PRB, and PRC,
each with different cellular activities.
48-52
In normal human breast tissue, the ratio of PRA:PRB is
approximately 1:1.
50, 53
This ratio is altered in a large percentage of breast cancer cells and is a
risk for breast cancer.
50, 53, 54
In contrast to progesterone, synthetic progestins alter the normal
PRA:PRB ratio,
55-57
which may be a mechanism by which synthetic progestins increase the risk
for breast cancer.

Synthetic progestins and progesterone have a number of differences in their molecular and
pharmacological effects on breast tissue, as some of the procarcinogenic effects of synthetic
progestins contrast with the anticarcinogenic properties of progesterone.
8, 16, 22, 24-26, 31, 33, 40, 58-70
3) Breast Cancer and Cardiovascular Disease Risks
Risk for Breast Cancer with Synthetic Progestins
Many studies have assessed the risk for breast cancer with the use of a synthetic progestin for
HRT. Despite significant variability in study design, synthetic progestins have been clearly
associated with an increased risk for breast cancer.
7, 8, 58, 71-98
The Women’s Health Initiative (WHI), a large randomized clinical trial, demonstrated that a
synthetic progestin, MPA, as a component of HRT significantly increased the risk for breast
cancer (relative risk [RR] = 1.26, 95% confidence interval [CI]: 1.00–1.59).
71-74
This trial confirmed
results from numerous other groups demonstrating that a synthetic progestin significantly
increases breast cancer risk.
7, 75, 98
In addition, higher doses of progestins, testosterone-derived
synthetic progestins, and progestin-only regimens further increase the risk for breast cancer.
8, 75-
77, 80, 91
The Nurses’ Health Study, which followed 58 000 postmenopausal women for 16 years
(725 000 person-years), found that, compared with women who never used hormones, use of
unopposed postmenopausal estrogen from ages 50 to 60 years increased the risk for breast
cancer to age 70 years by 23% (95% CI: 6–42). The addition of a synthetic progestin to the
estrogen replacement resulted in a tripling of the risk for breast cancer (67% increased risk) (95%
CI: 18–136).
98
Ross et al compared the risk for breast cancer in 1897 women on combined estrogen and
synthetic progestin with 1637 control patients who had never used HRT. Synthetic progestin use
increased the risk for breast cancer by approximately 25% for each 5 years of use compared with
estrogen alone (RR = 1.25, 95% CI: 1.02–1.18).
82
In a meta-analysis of 61 studies, Lee et al
found a consistently increased risk for breast cancer with synthetic HRT, with an average
increase of 7.6% per year of use (95% CI: 1.070–1.082), and also found that higher doses of
synthetic progestins conferred a significantly increased risk for breast cancer.
75
Ewertz et al
examined the risk for breast cancer for approximately 80 000 women aged 40 to 67 years from
1989 to 2002. For women older than 50 years, current use of synthetic HRT increased the risk for
breast cancer by 61% (95% CI: 1.38–1.88). Longer duration of use and the use of synthetic
progestins derived from testosterone were associated with increased risk.
76
Newcomb et al
studied the risk for breast cancer with synthetic HRT (80% used CEE and 86% used MPA) in
more than 5000 postmenopausal women aged 50 to 79 years. They found a significant increase
in breast cancer of 2% per year for the estrogen-only group (RR = 1.02/yr, 95% CI: 1.01–1.03/yr),
and a 4% increase per year if a synthetic progestin was used in addition to the estrogen (RR =
1.04/yr, 95% CI: 1.01–1.08/yr). Higher doses of progestin increased the risk for breast cancer,
and use of a progestin-only preparation doubled the risk for breast cancer (RR = 2.09, 95% CI:
1.07–4.07).
77
Risk for Breast Cancer with Bioidentical Progesterone
Progesterone and synthetic progestins have generally indistinguishable effects on endometrial
tissue. However, as discussed above, there is significant evidence that progesterone and
synthetic progestins have differing effects on breast tissue proliferation. Thus, progesterone and
synthetic progestins would be expected to carry different risks for breast cancer. Although no
randomized, controlled trials were identified that directly compared the risks for breast cancer
between progesterone and synthetic progestins, large-scale observational trials
58, 59
and
randomized placebo control primate trials
16
do show significant differences. Furthermore, in
contrast to the demonstrated increased risk for breast cancer with synthetic progestins,
7, 8, 58, 71-98
studies have consistently shown a decreased risk for breast cancer with progesterone.
22, 23, 25, 60,
61, 66-70, 99-101
In 2007, Fournier et al reported an association between various forms of HRT and the incidence
of breast cancer in more than 80 000 postmenopausal women who were followed for more than 8
postmenopausal years.
59
Compared with women who had never used any HRT, women who

used estrogen only (various preparations) had a nonsignificant increase of 1.29 times the risk for
breast cancer (P = 0.73). If a synthetic progestin was used in combination with estrogen, the risk
for breast cancer increased significantly to 1.69 times that for control subjects (P = 0.01).
However, for women who used progesterone in combination with estrogen, the increased risk for
breast cancer was eliminated with a significant reduction in breast cancer risk compared with
synthetic progestin use (P = 0.001).
59
In a previous analysis of more than 50 000 postmenopausal women in the E3N-EPIC cohort,
Fournier et al found that the risk for breast cancer was significantly increased if synthetic
progestins were used (RR = 1.4), but was reduced if progesterone was used (RR = 0.9). There
was a significant difference in the risk for breast cancer between the use of estrogens combined
with synthetic progestins versus estrogens combined with progesterone (P < 0.001).
58
Wood et al investigated whether the increased breast cancer risk with synthetic progestins was
also seen when progesterone was used.
16
Postmenopausal primates were given placebo,
estradiol, estradiol and MPA, and estradiol and bioidentical progesterone, with each treatment for
2 months with a 1-month washout period. Ki67 expression is a biomarker for lobular and ductal
epithelial proliferation in the postmenopausal breast and is an important prognostic indicator in
human breast cancer.
102
Compared with placebo, significantly increased proliferation was found
with the combination of estrogen and MPA in both lobular (P = 0.009) and ductal (P = 0.006)
tissue, but was not seen with the combination of estrogen and progesterone. Intramammary gene
expressions of the proliferation markers Ki67 and cyclin B1 were also higher after treatment with
estrogen and MPA (4.9-fold increase, P = 0.007 and 4.3-fold increase, P = 0.002, respectively)
but not with estrogen and progesterone. Inoh et al investigated the protective effect of
progesterone and tamoxifen on estrogen- and diethylstilbestrol-induced breast cancer in rats. The
induction rate, multiplicity, and size of estrogen-induced mammary tumors were significantly
reduced by simultaneous administration of either tamoxifen or progesterone.
25
Chang et al examined the effects of estrogen and progesterone on women prior to breast surgery
in a double-blind, placebo-controlled study in which patients were given placebo, estrogen,
transdermal progesterone, or estrogen and transdermal progesterone for 10 to 13 days before
breast surgery. Estrogen increased cell proliferation rates by 230% (P < 0.05), but progesterone
decreased cell proliferation rates by 400% (P < 0.05). Progesterone, when given with estradiol,
inhibited the estrogen-induced breast cell proliferation.
22
Similarly, in a randomized, double-blind
study, Foidart et al also showed that progesterone eliminated estrogen-induced breast cell
proliferation (P = 0.001).
23
A prospective epidemiological study demonstrated a protective role for progesterone against
breast cancer.
99
In this study, 1083 women who had been treated for infertility were followed for
13 to 33 years. The premenopausal risk for breast cancer was 5.4 times higher in women who
had low progesterone levels compared with those with normal levels (95% CI: 1.1–49). The result
was significant, despite the fact that the high progesterone group had significantly more risk
factors for breast cancer than the low progesterone group, highlighting the importance of this
parameter. Moreover, there were 10 times as many deaths from cancer in the low progesterone
group compared with those with normal progesterone levels (95% CI: 1.3–422).
99
99 Women with
low progesterone have significantly worse breast cancer survival rates than those with more
optimal progesterone levels.
100, 101
In a prospective study, luteal phase progesterone levels in 5963 women were measured and
compared with subsequent risk for breast cancer. Progesterone was inversely associated with
breast cancer risk for the highest versus lowest tertile (RR = 0.40, 95% CI: 0.15–1.08, P for trend
= 0.077). This trend became significant in women with regular menses, which allowed for more
accurate timing of collection (RR = 0.12, 95% CI: 0.03–0.52, P = 0.005).
61
Other casecontrol
studies also found such a relationship.
66-70
Peck et al conducted a nested case-control study to examine third-trimester progesterone levels

and maternal risk of breast cancer in women who were pregnant between 1959 and 1966. Cases
(n = 194) were diagnosed with in situ or invasive breast cancer between 1969 and 1991. Controls
(n = 374) were matched to cases by age at the time of index pregnancy using randomized
recruitment. Increasing progesterone levels were associated with a decreased risk of breast
cancer. Relative to those with progesterone levels in the lowest quartile (< 124.25 ng/mL), those
in the highest quartile (> 269.97 ng/mL) had a 50% reduction in the incidence of breast cancer
(RR = 0.49, CI 0.22–1.1, P for trend = 0.08). The association was stronger for cancers diagnosed
at or before age 50 years (RR = 0.3, CI: 0.1–0.9, P for trend = 0.04).60 Preeclampsia, with its
associated increased progesterone levels, is also associated with a reduced risk for breast
cancer.
103-105
Estriol and the Risk for Breast Cancer
Estrogen effects are mediated through 2 different estrogen receptors: estrogen receptor-alpha
(ER-α) and estrogen receptor-beta (ER-ß).
106-111
Estrogen receptor-a promotes breast cell
proliferation, while ER-ß inhibits proliferation and prevents breast cancer development via G2 cell
cycle arrest.
106, 112-117
Estradiol equally activates ER-α and ER-ß, while estrone selectively activates ER-α at a ratio of
5:1.
118, 119
In contrast, estriol selectively binds ER-ß at a ratio of 3:1.
118, 119
This unique property of
estriol, in contrast to the selective ER-α binding by other estrogens,
107, 118, 121
imparts to estriol a
potential for breast cancer prevention,
59, 122-125
while other estrogens would be expected to
promote breast cancer.
106, 112-115, 126
As well as selectively binding ER-α, CEE components are
potent downregulators of ER-ß receptors.
114
Whether this activity is unique to CEE is unclear, but
it could potentially increase carcinogenic properties.
Furthermore, synthetic progestins synergistically downregulate ER-ß receptors,
114
a possible
mechanism underlying the breast-cancer-promoting effect of CEE in conjunction with synthetic
progestins. Conjugated equine estrogens also contains at least one particularly potent
carcinogenic estrogen, 4-hydroxy-equilenin, which promotes cancer by inducing DNA damage.
127-
131
Because of its differing effects on ER-α and ER-ß, we would expect that estriol would be less
likely to induce proliferative changes in breast tissue and to be associated with a reduced risk of
breast cancer.
40, 59, 80, 103-105, 122-125, 132-144
Only one in vitro study on an estrogen receptor-positive
breast cancer tissue cell line demonstrated a stimulatory effect of estriol as well as for estrone
and estradiol.
145
Melamed et al demonstrated that, when administered with estradiol, estriol may
have a unique ability to protect breast tissue from excessive estrogen-mediated stimulation.
Acting alone, estriol is a weak estrogen, but when given with estradiol, it functions as an
antiestrogen. Interestingly, estriol competitively inhibits estradiol binding and also inhibits
activated receptor binding to estrogen response elements, which limits transcription.
135
Patentable estriol-like selective estrogen receptors modulators (SERMs) are being developed to
prevent and treat breast cancer.
106, 112, 113, 115
Estriol and progesterone levels dramatically increase during pregnancy (an approximate 15-fold
increase in progesterone and a 1000-fold increase in estriol), and postpartum women continue to
produce higher levels of estriol than nulliparous women.
136
This increased exposure to
progesterone and estriol during and after pregnancy confers a significant long-term reduction in
the risk for breast cancer.
40, 103-105, 136-141
If these substances were carcinogenic, it would be
expected that pregnancy would increase the risk for breast cancer rather than protect against it.
Urinary estriol levels in postmenopausal women show an inverse correlation with the risk for
breast cancer in many,
125, 132-134, 142, 143, 146
but not all, studies.
147
Lemon et al demonstrated that estriol and/or tamoxifen, as opposed to other estrogens,
prevented the development of breast cancer in rats after the administration of carcinogens.
123, 124
Mueck et al compared the proliferative effects of different estrogens on human breast cancer cells
when combined with progesterone or synthetic progestins.
24
24 They found that progesterone
inhibited breast cancer cell proliferation at higher estrogen levels, but that synthetic progestins

had the potential to stimulate breast cancer cell proliferation when combined with the synthetic
estrogens equilin or 17-alpha-dihydroequilin, which are major components of CEE. This
demonstrates a mechanism for the particularly marked increased risk for breast cancer when
CEE is combined with a synthetic progestin.
In a large study of more than 30 000 women by Bakken et al, the use of estrogen-only HRT
increased the risk of breast cancer compared with that in nonusers (RR = 1.8, 95% CI: 1.1–2.9).
The addition of a synthetic progestin further increased breast cancer risk (RR = 2.5, 95% CI: 1.9–
3.2) while the use of an estriol-containing preparation was not associated with the risk of breast
cancer that was seen with other preparations (RR =1.0, 95% CI: 0.4–2.5).
144
In a large case-control study of 3345 women aged 50 to 74 years, the use of estrogen only,
estrogen and synthetic progestin, or progestin only was associated with a significantly increased
risk of breast cancer (RR = 1.94, 95% CI: 1.47–2.55; RR = 1.63, CI: 1.37–1.94; and RR = 1.59,
CI: 1.05–2.41, respectively). The risk of breast cancer among estriol users was, however, not
appreciably different than among nonusers (RR = 1.10, CI: 0.95–1.29).
80
Large-scale randomized
control trials are needed to quantify the effects of estriol in the risk of breast cancer.
Cardiovascular Risk with Synthetic Progestins versus Progesterone
The WHI study demonstrated that the addition of MPA to Premarin® (a CEE) resulted in a
substantial increase in the risk of heart attack and stroke.
71-73
This outcome with MPA is not
surprising because synthetic progestins produce negative cardiovascular effects and negate the
cardioprotective effects of estrogen.
71, 73, 148-172
Progesterone, in contrast, has the opposite effect
because it maintains and augments the cardioprotective effects of estrogen, thus decreasing the
risk for heart attack and stroke.
148-151, 153, 155, 157, 162, 165, 167, 173-178
One mechanism contributing to these opposing effects for cardiovascular risk is the differing
effects on lipids. Medroxyprogesterone acetate and other synthetic progestins generally negate
the positive lipid effects of estrogen and show a consistent reduction in HDL,
148, 153-159, 163
the most
important readily measured determinant of cardioprotection, while progesterone either maintains
or augments estrogen’s positive lipid and HDL effects.
148, 154, 155, 157, 173, 176
For instance, the PEPI
trial, a long-term randomized trial of HRT, compared a variety of cardiovascular effects including
lipid effects of both MPA and progesterone in combination with CEE. While all regimens were
associated with clinically significant improvements in lipoprotein levels, many of estrogen’s
beneficial effects on HDL-C were negated with the addition of MPA. The addition of progesterone
to CEE, however, was associated with significantly higher HDL-C levels than with MPA and CEE
(a notable sparing of estrogen’s beneficial effects) (P < 0.004).
154
Fahraeus et al compared the lipid effects of synthetic progestins with progesterone in 26
postmenopausal women who had been receiving cutaneous estradiol for 3 to 6 months. Women
received either 120 µg of l-norgestrel or 300 mg of progesterone sequentially for another 6
months. Compared with the use of progesterone, l-norgestrel resulted in significant reductions in
HDL and HDL-2 (P < 0.05).
155
Ottosson et al compared the lipid effects of estrogen when combined with either of 2 synthetic
progestins, or bioidentical progesterone.
148
Menopausal women were initially treated with 2 mg
estradiol valerate (cyclical) for 3 cycles, and then were randomized to receive MPA,
levonorgestrel, or progesterone. Serum lipids and lipoproteins were analyzed during the last days
of the third, fourth, and sixth cycles. Those receiving estrogen combined with levonorgestrel had
a significant reduction in HDL and HDL subfraction 2 (18% and 28%, respectively; P < 0.01), as
did those receiving MPA (8% and 17%, respectively; P < 0.01). Conversely, there were no
significant changes seen in the HDL and HDL subfraction levels with the use of progesterone.
148
Furthermore, a randomized trial by Saarikoski et al which compared the lipid effects in women
using the synthetic progestin norethisterone and progesterone, those on synthetic progestin had
a significant decrease in HDL, whereas those using progesterone had no decrease in HDL (P <
0.001).
153

A number of studies have shown that coronary artery spasm, which increases the risk for heart
attack and stroke, is reduced with the use of estrogen and/or progesterone.
149-151, 174, 179, 180
However, the addition of MPA to estrogen has the opposite effect, resulting in
vasoconstriction,
149-151, 174
thus increasing the risk for ischemic heart disease. Minshall et al
compared coronary hyperreactivity by infusing a thromboxane A2 mimetic in primates, which
were administered estradiol along with MPA or progesterone. When estradiol was given with
progesterone, the coronary arteries were protected against induced spasm. However, the
protective effect was lost when MPA was used instead of progesterone.
149
Miyagawa et al also compared the reactivity of coronary arteries in primates pretreated with
estradiol combined with either progesterone or MPA. None of the animals treated with bioidentical
progesterone experienced vasospasm, while all of those treated with MPA showed significant
vasospasm.
151
Mishra et al
150
also found that progesterone protected against coronary
hyperreactivity, while MPA had the opposite effect and induced coronary constriction.
In a blinded, randomized, crossover study, the effects of estrogen and progesterone were
compared with estrogen and MPA on exercise-induced myocardial ischemia in postmenopausal
women with coronary artery disease. Women were treated with estradiol for 4 weeks and then
randomized to receive either progesterone or MPA along with estradiol. After 10 days on the
combined treatment, the patients underwent a treadmill test. Patients were then crossed over to
the opposite treatment, and the treadmill exercise was repeated. Exercise time to myocardial
ischemia was significantly increased in the progesterone group compared with the MPA group (P
< 0.001).
162
Adams et al
152, 175
examined the cardioprotective effects of CEE and progesterone versus CEE
and MPA in primates fed atherogenic diets for 30 months. The CEE and progesterone
combination resulted in a 50% reduction in atherosclerotic plaques in the coronary arteries (P <
0.05).
175
This result was independent of changes in lipid concentrations. However, when MPA
was combined with the CEE, almost all the cardioprotective effect (atherosclerotic plaque
reduction) was reversed (P < 0.05).
152
Other studies have shown that progesterone by itself,
167,
177, 181
or in combination with estrogen,
152, 175, 177
inhibits atherosclerotic plaque formation.
Synthetic progestins, in contrast, have a completely opposite effect: they promote atherosclerotic
plaque formation and prevent the plaque-inhibiting and lipid-lowering actions of estrogen.
152, 164,
166
Transdermal estradiol, when given with or without oral progesterone, has no detrimental effects
on coagulation and no observed increased risk for venous thromboembolism (VTE).
161, 182-184
This
result is in contrast to an increased risk for VTE with CEE, with or without synthetic progestin,
which significantly increases the risk for VTE, whether both are given orally (eg, oral estrogen and
oral synthetic progestin),
71, 73, 160, 171
as transdermal estrogen and oral synthetic progestin,
161
or
both estrogen and synthetic progestin given transdermally.
185, 186
Canonico et al compared the
risk for VTE with different forms of HRT in 271 cases and 610 controls. They found that
transdermal estradiol and oral progesterone or pregnane derivatives (progestins derived from
progesterone) were not associated with VTE risk (RR = 0.7; 95% CI: 0.3–1.9 and RR = 0.9; 95%
CI: 0.4–2.3, respectively). In contrast, the use of nonpregnane derivatives increased VTE risk 4-
fold (RR = 3.9; 95% CI: 1.5–10).
161
Medroxyprogesterone acetate also has undesirable intrinsic glucocorticoid activity,
187, 188
whereas
progesterone does not have such negative effects and is a competitive inhibitor of aldosterone,
which is generally a desirable effect.
189
No changes in blood pressure are observed with
progesterone in normotensive postmenopausal women, but a slight reduction in blood pressure is
shown in hypertensive women.
190, 191
Synthetic progestins can significantly increase insulin
resistance,
167-170, 191
when compared with estrogen and progesterone.
169, 170, 191
The expression of vascular cell adhesion molecule-1 (VCAM-1) is one of the earliest events in the
atherogenic process. Otsuki et al compared the effects of progesterone and MPA on VCAM-1

expression and found that progesterone inhibited VCAM-1. No such effect was observed with
MPA (P < 0.001).
165
Discussion
Physicians must translate both basic science results and clinical outcomes to decide on the
safest, most efficacious treatment for patients. Evidence-based medicine involves the synthesis
of all available data when comparing therapeutic options for patients. Evidence-based medicine
does not mean that data should be ignored until a randomized control trial of a particular size and
duration is completed. Rather, it demands an assessment of the current available data to decide
which therapies are likely to carry the greatest benefits and the lowest risks for patients.
Progesterone, compared with MPA, is associated with greater efficacy, patient satisfaction, and
quality of life. More importantly, molecular differences between synthetic progestins and
progesterone result in differences in their pharmacological effects on breast tissue. Some of the
procarcinogenic effects of synthetic progestins contrast with the anticarcinogenic properties of
progesterone, which result in disparate clinical effects on the risk of breast cancer. Progesterone
has an antiproliferative, antiestrogenic effect on both the endometrium and breast tissue, while
synthetic progestins have antiproliferative, antiestrogenic effects on endometrial tissue, but often
have a proliferative estrogenic effect on breast tissue. Synthetic progestins show increased
estrogen-induced breast tissue proliferation and a risk for breast cancer, whereas progesterone
inhibits breast tissue proliferation and reduces the risk for breast cancer.
Until recently, estriol was available in the United States as a compounded prescription, but was
banned in January 2008 by the FDA, which stated that it was a new, unapproved drug with
unknown safety and effectiveness, although its symptomatic efficacy is generally not in
question.
192-196
The FDA has not received a single report of an adverse event in more than 30
years of estriol use. Estriol is also the subject of a US Pharmacopeia monograph. The FDA
Modernization Act of 1997 clearly indicated that drugs with a US Pharmacopeia monograph could
be compounded. It appears that the FDA took action, not because estriol is at least as safe and
effective as current estrogens on the market, but in response to what was considered
unsupported claims that estriol was safer than current forms of estrogen replacement and
because there is no standardized dose. Estriol has unique physiologic properties associated with
a reduction in the risk of breast cancer, and combining estriol with estradiol in hormone
replacement preparations would be expected to decrease the risk for breast cancer.
In cardiovascular disease, synthetic progestins, as opposed to progesterone, negate the
beneficial lipid and vascular effects of estrogen. Transdermal bioidentical estrogen and
progesterone are associated with beneficial cardiovascular and metabolic effects compared with
the use of CEE and synthetic progestins.
Based on both physiological results and clinical outcomes, current evidence demonstrates that
bioidentical hormones are associated with lower risks than their nonbioidentical counterparts.
Until there is evidence to the contrary, current evidence dictates that bioidentical hormones are
the preferred method of HRT.
Conclusion
A thorough review of the medical literature supports the claim that bioidentical hormones have
some distinctly different, often opposite, physiological effects to those of their synthetic
counterparts. With respect to the risk for breast cancer, heart disease, heart attack, and stroke,
substantial scientific and medical evidence demonstrates that bioidentical hormones are safer
and more efficacious forms of HRT than commonly used synthetic versions. More randomized
control trials of substantial size and length will be needed to further delineate these differences.
Acknowledgments
The author wishes to thank Duaine Jackola, PhD, of ScienceDocs for his editing contribution.
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Kent Holtorf, MD, Holtorf Medical Group, Inc., 23456 Hawthorne Blvd., Suite 160, Torrance, CA
90505. Tel: 310-375-2705 Fax: 310-375-2701 E-mail: kholtorf@cox.net
Postgraduate Medicine: Volume 121: No.1
The Bioidentical Hormone Debate:
Are Bioidentical Hormones (Estradiol, Estriol, and Progesterone) Safer or More Efficacious than
Commonly Used Synthetic Versions in Hormone Replacement Therapy?
Kent Holtorf, MD
Abstract:
Background: The use of bioidentical hormones, including progesterone, estradiol, and estriol, in
hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their
relative safety compared with traditional synthetic and animal-derived versions, such as
conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic
progestins. Proponents for bioidentical hormones claim that they are safer than comparable
synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration
and The Endocrine Society, there is little or no evidence to support claims that bioidentical
hormones are safer or more effective. Objective: This paper aimed to evaluate the evidence
comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the
commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast
tissue, and risks for breast cancer and cardiovascular disease. Methods: Published papers were
identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included

keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that
compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in
vitro results, were selected. Results: Patients report greater satisfaction with HRTs that contain
progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have
some distinctly different, potentially opposite, physiological effects compared with their synthetic
counterparts, which have different chemical structures. Both physiological and clinical data have
indicated that progesterone is associated with a diminished risk for breast cancer, compared with
the increased risk associated with synthetic progestins. Estriol has some unique physiological
effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry
less risk for breast cancer, although no randomized controlled trials have been documented.
Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with
progesterone. Conclusion: Physiological data and clinical outcomes demonstrate that
bioidentical hormones are associated with lower risks, including the risk of breast cancer and
cardiovascular disease, and are more efficacious than their synthetic and animalderived
counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred
method of HRT. Further randomized controlled trials are needed to delineate these differences
more clearly.
Introduction
The relative safety of bioidentical hormone replacement compared with traditional synthetic and
animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone
acetate (MPA), and other synthetic progestins is the subject of intense debate. According to The
Endocrine Society Position Statement, there is little or no evidence to support the claim that
bioidentical hormones are safer or more effective than the commonly used synthetic versions of
hormone replacement therapy (HRT).
1
Furthermore, the US Food and Drug Administration (FDA)
has ordered pharmacies to stop providing estriol, stating that it is a new, unapproved drug with
unknown safety and effectiveness.
Nevertheless, estriol has been used for decades without reported safety concerns and is a
component of medications approved for use worldwide. The FDA has acknowledged that it is
unaware of any adverse events associated with the use of compounded medications containing
estriol, and US Congress is considering a resolution (HR342) to reverse the FDA’s decision to
restrict its use. Claims by The Endocrine Society and the FDA are in direct contrast to those of
proponents of bioidentical hormones, who argue that these hormones are safer than comparable
synthetic versions of HRT. Such claims are not fully supported, which can be confusing for
patients and physicians.
One major reason for a lack of conclusive data is that, until recently, progestogens were lumped
together because of a commonly held belief that different forms of progestogens would have
identical physiological effects and risks, because they all mediate effects via the same
(progesterone) receptor. This view also applies to the different forms of estrogen, which are
commonly grouped together and referred to as estrogen replacement therapy.
The term “bioidentical HRT” refers to the use of hormones that are exact copies of endogenous
human hormones, including estriol, estradiol, and progesterone, as opposed to synthetic versions
with different chemical structures or nonhuman versions, such as CEE. Bioidentical hormones are
also often referred to as “natural hormones,” which can be confusing because bioidentical
hormones are synthesized, while some estrogens from a natural source, such as equine urine,
are not considered bioidentical because many of their components are foreign to the human
body.
This review will examine the differences between the bioidentical hormones estriol, estradiol, and
progesterone when used as components of HRT compared with synthetic or nonidentical
hormones such as CEE and synthetic progestins, including MPA. The article attempts to
determine whether there is any supporting evidence that bioidentical hormones are a potentially
safer or more effective form of HRT than the commonly used synthetic versions.

Methods
Definitions
Bioidentical hormones have a chemical structure identical to human hormones but are chemically
synthesized, such as progesterone, estriol, and estradiol. Nonbioidentical hormones are not
structurally identical to human hormones and may either be chemically synthesized, such as
MPA, or derived from a nonhuman source, such as CEE.
Databases and Keywords
Literature searches were conducted for HRT formularies, focusing on those that either are or
have been used in the United States. Published papers identified for review by
PubMed/MEDLINE, Google Scholar, and Cochrane database searches included the keywords:
“bioidentical hormones,” “synthetic hormones,” “progestin,” “menopausal hormone replacement,”
“hormone replacement therapy,” “HRT,” “estriol,” “progesterone,” “natural hormones,” “conjugated
equine estrogens,” “medroxyprogesterone acetate,” “breast cancer,” and “cardiovascular
disease.”
Comparisons
Published papers that focused on 3 key areas were identified: 1) clinical efficacy, 2) physiologic
actions on breast tissue, and 3) risks for breast cancer and cardiovascular disease. Papers
included human clinical studies that compared bioidentical and nonbioidentical hormones, animal
studies based on similar comparisons, and in vitro experimental work that focused on
physiological or biochemical aspects of the hormones.
Results
1) Symptomatic Efficacy of Synthetic Progestins versus Progesterone
Four studies of patients using HRT, including either progesterone or MPA, compared efficacy,
patient satisfaction, and quality of life. Women in all 4 studies reported greater satisfaction, fewer
side effects, and improved quality of life when they were switched from synthetic progestins to
progesterone replacement.
2-6
In a cross-sectional survey, Fitzpatrick et al compared patient
satisfaction and quality of life, as well as other somatic and psychological symptoms (ie, anxiety,
depression, sleep problems, menstrual bleeding, vasomotor symptoms, cognitive difficulties,
attraction, and sexual functioning) in 176 menopausal women on HRT with MPA versus HRT with
progesterone.
2
Significant differences were seen for all somatic, vasomotor, and psychological
symptoms, except for attraction, when bioidentical progesterone was used rather than MPA (P <
0.001).
The effect of progesterone compared with MPA included a 30% reduction in sleep problems, a
50% reduction in anxiety, a 60% reduction in depression, a 30% reduction in somatic symptoms,
a 25% reduction in menstrual bleeding, a 40% reduction in cognitive difficulties, and a 30%
improvement in sexual function. Overall, 65% of women felt that HRT combined with
progesterone was better than the HRT combined with MPA.
2
In a randomized study comparing HRT with MPA or progesterone in 23 postmenopausal women
with no mood disorders such as depression or anxiety, Cummings and Brizendine found
significantly more negative somatic effects but no differences in mood assessment with synthetic
hormones. These negative effects included increased vaginal bleeding (P = 0.003) and increased
breast tenderness (P = 0.02), with a trend for increased hot flashes with the use of MPA
compared with progesterone.
3
In the 3-year, double-blind, placebo-controlled Postmenopausal
Estrogen/Progestin Interventions (PEPI) trial, 875 menopausal women received either placebo,
CEE with MPA (cyclic or continuous), or progesterone (cyclic). Those taking progesterone had
fewer episodes of excessive bleeding than those on MPA (either continuous or cyclic),
4
but no
differences were noted in symptomatic relief.
5
2) Differing Physiological Effects of Bioidentical Progesterone and
Synthetic Progestins
Progesterone and synthetic progestins generally have indistinguishable effects on endometrial
tissue, which are not the focus of this review. Studies that compared the physiological differences
in breast tissue of those on progesterone, with those on other progestins, have the potential to

predict differing risks of breast cancer. While variations in methodology and study design are
considerable, most of the literature demonstrates physiological differences between progestins
and progesterone and their effects on breast tissue.
Synthetic progestins have potential antiapoptotic effects and may significantly increase estrogen-
stimulated breast cell mitotic activity and proliferation.
7-21
In contrast, progesterone inhibits
estrogen-stimulated breast epithelial cells.
16, 22-28
Progesterone also downregulates estrogen
receptor-1 (ER-1) in the breast,
27-29
induces breast cancer cell apoptosis,
30, 31
diminishes breast
cell mitotic activity,
7, 16, 22-24, 26-28, 31, 32
and arrests human breast cancer cells in the G1 phase by
upregulating cyclin-dependent kinase inhibitors and downregulating cyclin D1.
23, 32
Synthetic progestins, in contrast, upregulate cyclin D1
21
and increase breast cell proliferation.
7-21
Progesterone consistently demonstrates antiestrogenic activity in breast tissue.
7, 16, 22, 24-29, 31-34
This result is generally in contrast to that for synthetic progestins, especially the 19-
nortestosteronederived progestins, which bind to estrogen receptors in breast tissue (but not in
endometrial tissue) and display significant intrinsic estrogenic properties in breast but not
endometrial tissue.
11, 23, 35-39
Synthetic progestins may also increase the conversion of weaker endogenous estrogens into
more potent estrogens,
7, 40-45
potentially contributing to their carcinogenic effects, which are not
apparent with progesterone. Synthetic progestins may promote the formation of the genotoxic
estrogen metabolite 16-hydroxyestrone.
41
Synthetic progestins, especially MPA, stimulate the
conversion of inactive estrone sulfate into active estrone by stimulating sulfatase,
43, 44
as well as
increasing 17-beta-hydroxysteroid reductase activity,
7, 40, 42, 43, 45
which in turn increases the
intracellular formation of more potent estrogens and potentially increases breast cancer risk.
Progesterone has an opposite effect, stimulating the oxidative isoform of 17-beta-hydroxysteroid
dehydrogenase, which increases the intracellular conversion of potent estrogens to their less
potent counterparts.
34, 46, 47
At least 3 subclasses of progesterone receptors (PR) have been identified: PRA, PRB, and PRC,
each with different cellular activities.
48-52
In normal human breast tissue, the ratio of PRA:PRB is
approximately 1:1.
50, 53
This ratio is altered in a large percentage of breast cancer cells and is a
risk for breast cancer.
50, 53, 54
In contrast to progesterone, synthetic progestins alter the normal
PRA:PRB ratio,
55-57
which may be a mechanism by which synthetic progestins increase the risk
for breast cancer.
Synthetic progestins and progesterone have a number of differences in their molecular and
pharmacological effects on breast tissue, as some of the procarcinogenic effects of synthetic
progestins contrast with the anticarcinogenic properties of progesterone.
8, 16, 22, 24-26, 31, 33, 40, 58-70
3) Breast Cancer and Cardiovascular Disease Risks
Risk for Breast Cancer with Synthetic Progestins
Many studies have assessed the risk for breast cancer with the use of a synthetic progestin for
HRT. Despite significant variability in study design, synthetic progestins have been clearly
associated with an increased risk for breast cancer.
7, 8, 58, 71-98
The Women’s Health Initiative (WHI), a large randomized clinical trial, demonstrated that a
synthetic progestin, MPA, as a component of HRT significantly increased the risk for breast
cancer (relative risk [RR] = 1.26, 95% confidence interval [CI]: 1.00–1.59).
71-74
This trial confirmed
results from numerous other groups demonstrating that a synthetic progestin significantly
increases breast cancer risk.
7, 75, 98
In addition, higher doses of progestins, testosterone-derived
synthetic progestins, and progestin-only regimens further increase the risk for breast cancer.
8, 75-
77, 80, 91
The Nurses’ Health Study, which followed 58 000 postmenopausal women for 16 years
(725 000 person-years), found that, compared with women who never used hormones, use of
unopposed postmenopausal estrogen from ages 50 to 60 years increased the risk for breast
cancer to age 70 years by 23% (95% CI: 6–42). The addition of a synthetic progestin to the
estrogen replacement resulted in a tripling of the risk for breast cancer (67% increased risk) (95%

CI: 18–136).
98
Ross et al compared the risk for breast cancer in 1897 women on combined estrogen and
synthetic progestin with 1637 control patients who had never used HRT. Synthetic progestin use
increased the risk for breast cancer by approximately 25% for each 5 years of use compared with
estrogen alone (RR = 1.25, 95% CI: 1.02–1.18).
82
In a meta-analysis of 61 studies, Lee et al
found a consistently increased risk for breast cancer with synthetic HRT, with an average
increase of 7.6% per year of use (95% CI: 1.070–1.082), and also found that higher doses of
synthetic progestins conferred a significantly increased risk for breast cancer.
75
Ewertz et al
examined the risk for breast cancer for approximately 80 000 women aged 40 to 67 years from
1989 to 2002. For women older than 50 years, current use of synthetic HRT increased the risk for
breast cancer by 61% (95% CI: 1.38–1.88). Longer duration of use and the use of synthetic
progestins derived from testosterone were associated with increased risk.
76
Newcomb et al
studied the risk for breast cancer with synthetic HRT (80% used CEE and 86% used MPA) in
more than 5000 postmenopausal women aged 50 to 79 years. They found a significant increase
in breast cancer of 2% per year for the estrogen-only group (RR = 1.02/yr, 95% CI: 1.01–1.03/yr),
and a 4% increase per year if a synthetic progestin was used in addition to the estrogen (RR =
1.04/yr, 95% CI: 1.01–1.08/yr). Higher doses of progestin increased the risk for breast cancer,
and use of a progestin-only preparation doubled the risk for breast cancer (RR = 2.09, 95% CI:
1.07–4.07).
77
Risk for Breast Cancer with Bioidentical Progesterone
Progesterone and synthetic progestins have generally indistinguishable effects on endometrial
tissue. However, as discussed above, there is significant evidence that progesterone and
synthetic progestins have differing effects on breast tissue proliferation. Thus, progesterone and
synthetic progestins would be expected to carry different risks for breast cancer. Although no
randomized, controlled trials were identified that directly compared the risks for breast cancer
between progesterone and synthetic progestins, large-scale observational trials
58, 59
and
randomized placebo control primate trials
16
do show significant differences. Furthermore, in
contrast to the demonstrated increased risk for breast cancer with synthetic progestins,
7, 8, 58, 71-98
studies have consistently shown a decreased risk for breast cancer with progesterone.
22, 23, 25, 60,
61, 66-70, 99-101
In 2007, Fournier et al reported an association between various forms of HRT and the incidence
of breast cancer in more than 80 000 postmenopausal women who were followed for more than 8
postmenopausal years.
59
Compared with women who had never used any HRT, women who
used estrogen only (various preparations) had a nonsignificant increase of 1.29 times the risk for
breast cancer (P = 0.73). If a synthetic progestin was used in combination with estrogen, the risk
for breast cancer increased significantly to 1.69 times that for control subjects (P = 0.01).
However, for women who used progesterone in combination with estrogen, the increased risk for
breast cancer was eliminated with a significant reduction in breast cancer risk compared with
synthetic progestin use (P = 0.001).
59
In a previous analysis of more than 50 000 postmenopausal women in the E3N-EPIC cohort,
Fournier et al found that the risk for breast cancer was significantly increased if synthetic
progestins were used (RR = 1.4), but was reduced if progesterone was used (RR = 0.9). There
was a significant difference in the risk for breast cancer between the use of estrogens combined
with synthetic progestins versus estrogens combined with progesterone (P < 0.001).
58
Wood et al investigated whether the increased breast cancer risk with synthetic progestins was
also seen when progesterone was used.
16
Postmenopausal primates were given placebo,
estradiol, estradiol and MPA, and estradiol and bioidentical progesterone, with each treatment for
2 months with a 1-month washout period. Ki67 expression is a biomarker for lobular and ductal
epithelial proliferation in the postmenopausal breast and is an important prognostic indicator in
human breast cancer.
102
Compared with placebo, significantly increased proliferation was found
with the combination of estrogen and MPA in both lobular (P = 0.009) and ductal (P = 0.006)
tissue, but was not seen with the combination of estrogen and progesterone. Intramammary gene

expressions of the proliferation markers Ki67 and cyclin B1 were also higher after treatment with
estrogen and MPA (4.9-fold increase, P = 0.007 and 4.3-fold increase, P = 0.002, respectively)
but not with estrogen and progesterone. Inoh et al investigated the protective effect of
progesterone and tamoxifen on estrogen- and diethylstilbestrol-induced breast cancer in rats. The
induction rate, multiplicity, and size of estrogen-induced mammary tumors were significantly
reduced by simultaneous administration of either tamoxifen or progesterone.
25
Chang et al examined the effects of estrogen and progesterone on women prior to breast surgery
in a double-blind, placebo-controlled study in which patients were given placebo, estrogen,
transdermal progesterone, or estrogen and transdermal progesterone for 10 to 13 days before
breast surgery. Estrogen increased cell proliferation rates by 230% (P < 0.05), but progesterone
decreased cell proliferation rates by 400% (P < 0.05). Progesterone, when given with estradiol,
inhibited the estrogen-induced breast cell proliferation.
22
Similarly, in a randomized, double-blind
study, Foidart et al also showed that progesterone eliminated estrogen-induced breast cell
proliferation (P = 0.001).
23
A prospective epidemiological study demonstrated a protective role for progesterone against
breast cancer.
99
In this study, 1083 women who had been treated for infertility were followed for
13 to 33 years. The premenopausal risk for breast cancer was 5.4 times higher in women who
had low progesterone levels compared with those with normal levels (95% CI: 1.1–49). The result
was significant, despite the fact that the high progesterone group had significantly more risk
factors for breast cancer than the low progesterone group, highlighting the importance of this
parameter. Moreover, there were 10 times as many deaths from cancer in the low progesterone
group compared with those with normal progesterone levels (95% CI: 1.3–422).
99
99 Women with
low progesterone have significantly worse breast cancer survival rates than those with more
optimal progesterone levels.
100, 101
In a prospective study, luteal phase progesterone levels in 5963 women were measured and
compared with subsequent risk for breast cancer. Progesterone was inversely associated with
breast cancer risk for the highest versus lowest tertile (RR = 0.40, 95% CI: 0.15–1.08, P for trend
= 0.077). This trend became significant in women with regular menses, which allowed for more
accurate timing of collection (RR = 0.12, 95% CI: 0.03–0.52, P = 0.005).
61
Other casecontrol
studies also found such a relationship.
66-70
Peck et al conducted a nested case-control study to examine third-trimester progesterone levels
and maternal risk of breast cancer in women who were pregnant between 1959 and 1966. Cases
(n = 194) were diagnosed with in situ or invasive breast cancer between 1969 and 1991. Controls
(n = 374) were matched to cases by age at the time of index pregnancy using randomized
recruitment. Increasing progesterone levels were associated with a decreased risk of breast
cancer. Relative to those with progesterone levels in the lowest quartile (< 124.25 ng/mL), those
in the highest quartile (> 269.97 ng/mL) had a 50% reduction in the incidence of breast cancer
(RR = 0.49, CI 0.22–1.1, P for trend = 0.08). The association was stronger for cancers diagnosed
at or before age 50 years (RR = 0.3, CI: 0.1–0.9, P for trend = 0.04).60 Preeclampsia, with its
associated increased progesterone levels, is also associated with a reduced risk for breast
cancer.
103-105
Estriol and the Risk for Breast Cancer
Estrogen effects are mediated through 2 different estrogen receptors: estrogen receptor-alpha
(ER-α) and estrogen receptor-beta (ER-ß).
106-111
Estrogen receptor-a promotes breast cell
proliferation, while ER-ß inhibits proliferation and prevents breast cancer development via G2 cell
cycle arrest.
106, 112-117
Estradiol equally activates ER-α and ER-ß, while estrone selectively activates ER-α at a ratio of
5:1.
118, 119
In contrast, estriol selectively binds ER-ß at a ratio of 3:1.
118, 119
This unique property of
estriol, in contrast to the selective ER-α binding by other estrogens,
107, 118, 121
imparts to estriol a
potential for breast cancer prevention,
59, 122-125
while other estrogens would be expected to
promote breast cancer.
106, 112-115, 126
As well as selectively binding ER-α, CEE components are

potent downregulators of ER-ß receptors.
114
Whether this activity is unique to CEE is unclear, but
it could potentially increase carcinogenic properties.
Furthermore, synthetic progestins synergistically downregulate ER-ß receptors,
114
a possible
mechanism underlying the breast-cancer-promoting effect of CEE in conjunction with synthetic
progestins. Conjugated equine estrogens also contains at least one particularly potent
carcinogenic estrogen, 4-hydroxy-equilenin, which promotes cancer by inducing DNA damage.
127-
131
Because of its differing effects on ER-α and ER-ß, we would expect that estriol would be less
likely to induce proliferative changes in breast tissue and to be associated with a reduced risk of
breast cancer.
40, 59, 80, 103-105, 122-125, 132-144
Only one in vitro study on an estrogen receptor-positive
breast cancer tissue cell line demonstrated a stimulatory effect of estriol as well as for estrone
and estradiol.
145
Melamed et al demonstrated that, when administered with estradiol, estriol may
have a unique ability to protect breast tissue from excessive estrogen-mediated stimulation.
Acting alone, estriol is a weak estrogen, but when given with estradiol, it functions as an
antiestrogen. Interestingly, estriol competitively inhibits estradiol binding and also inhibits
activated receptor binding to estrogen response elements, which limits transcription.
135
Patentable estriol-like selective estrogen receptors modulators (SERMs) are being developed to
prevent and treat breast cancer.
106, 112, 113, 115
Estriol and progesterone levels dramatically increase during pregnancy (an approximate 15-fold
increase in progesterone and a 1000-fold increase in estriol), and postpartum women continue to
produce higher levels of estriol than nulliparous women.
136
This increased exposure to
progesterone and estriol during and after pregnancy confers a significant long-term reduction in
the risk for breast cancer.
40, 103-105, 136-141
If these substances were carcinogenic, it would be
expected that pregnancy would increase the risk for breast cancer rather than protect against it.
Urinary estriol levels in postmenopausal women show an inverse correlation with the risk for
breast cancer in many,
125, 132-134, 142, 143, 146
but not all, studies.
147
Lemon et al demonstrated that estriol and/or tamoxifen, as opposed to other estrogens,
prevented the development of breast cancer in rats after the administration of carcinogens.
123, 124
Mueck et al compared the proliferative effects of different estrogens on human breast cancer cells
when combined with progesterone or synthetic progestins.
24
24 They found that progesterone
inhibited breast cancer cell proliferation at higher estrogen levels, but that synthetic progestins
had the potential to stimulate breast cancer cell proliferation when combined with the synthetic
estrogens equilin or 17-alpha-dihydroequilin, which are major components of CEE. This
demonstrates a mechanism for the particularly marked increased risk for breast cancer when
CEE is combined with a synthetic progestin.
In a large study of more than 30 000 women by Bakken et al, the use of estrogen-only HRT
increased the risk of breast cancer compared with that in nonusers (RR = 1.8, 95% CI: 1.1–2.9).
The addition of a synthetic progestin further increased breast cancer risk (RR = 2.5, 95% CI: 1.9–
3.2) while the use of an estriol-containing preparation was not associated with the risk of breast
cancer that was seen with other preparations (RR =1.0, 95% CI: 0.4–2.5).
144
In a large case-control study of 3345 women aged 50 to 74 years, the use of estrogen only,
estrogen and synthetic progestin, or progestin only was associated with a significantly increased
risk of breast cancer (RR = 1.94, 95% CI: 1.47–2.55; RR = 1.63, CI: 1.37–1.94; and RR = 1.59,
CI: 1.05–2.41, respectively). The risk of breast cancer among estriol users was, however, not
appreciably different than among nonusers (RR = 1.10, CI: 0.95–1.29).
80
Large-scale randomized
control trials are needed to quantify the effects of estriol in the risk of breast cancer.
Cardiovascular Risk with Synthetic Progestins versus Progesterone
The WHI study demonstrated that the addition of MPA to Premarin® (a CEE) resulted in a
substantial increase in the risk of heart attack and stroke.
71-73
This outcome with MPA is not
surprising because synthetic progestins produce negative cardiovascular effects and negate the

cardioprotective effects of estrogen.
71, 73, 148-172
Progesterone, in contrast, has the opposite effect
because it maintains and augments the cardioprotective effects of estrogen, thus decreasing the
risk for heart attack and stroke.
148-151, 153, 155, 157, 162, 165, 167, 173-178
One mechanism contributing to these opposing effects for cardiovascular risk is the differing
effects on lipids. Medroxyprogesterone acetate and other synthetic progestins generally negate
the positive lipid effects of estrogen and show a consistent reduction in HDL,
148, 153-159, 163
the most
important readily measured determinant of cardioprotection, while progesterone either maintains
or augments estrogen’s positive lipid and HDL effects.
148, 154, 155, 157, 173, 176
For instance, the PEPI
trial, a long-term randomized trial of HRT, compared a variety of cardiovascular effects including
lipid effects of both MPA and progesterone in combination with CEE. While all regimens were
associated with clinically significant improvements in lipoprotein levels, many of estrogen’s
beneficial effects on HDL-C were negated with the addition of MPA. The addition of progesterone
to CEE, however, was associated with significantly higher HDL-C levels than with MPA and CEE
(a notable sparing of estrogen’s beneficial effects) (P < 0.004).
154
Fahraeus et al compared the lipid effects of synthetic progestins with progesterone in 26
postmenopausal women who had been receiving cutaneous estradiol for 3 to 6 months. Women
received either 120 µg of l-norgestrel or 300 mg of progesterone sequentially for another 6
months. Compared with the use of progesterone, l-norgestrel resulted in significant reductions in
HDL and HDL-2 (P < 0.05).
155
Ottosson et al compared the lipid effects of estrogen when combined with either of 2 synthetic
progestins, or bioidentical progesterone.
148
Menopausal women were initially treated with 2 mg
estradiol valerate (cyclical) for 3 cycles, and then were randomized to receive MPA,
levonorgestrel, or progesterone. Serum lipids and lipoproteins were analyzed during the last days
of the third, fourth, and sixth cycles. Those receiving estrogen combined with levonorgestrel had
a significant reduction in HDL and HDL subfraction 2 (18% and 28%, respectively; P < 0.01), as
did those receiving MPA (8% and 17%, respectively; P < 0.01). Conversely, there were no
significant changes seen in the HDL and HDL subfraction levels with the use of progesterone.
148
Furthermore, a randomized trial by Saarikoski et al which compared the lipid effects in women
using the synthetic progestin norethisterone and progesterone, those on synthetic progestin had
a significant decrease in HDL, whereas those using progesterone had no decrease in HDL (P <
0.001).
153
A number of studies have shown that coronary artery spasm, which increases the risk for heart
attack and stroke, is reduced with the use of estrogen and/or progesterone.
149-151, 174, 179, 180
However, the addition of MPA to estrogen has the opposite effect, resulting in
vasoconstriction,
149-151, 174
thus increasing the risk for ischemic heart disease. Minshall et al
compared coronary hyperreactivity by infusing a thromboxane A2 mimetic in primates, which
were administered estradiol along with MPA or progesterone. When estradiol was given with
progesterone, the coronary arteries were protected against induced spasm. However, the
protective effect was lost when MPA was used instead of progesterone.
149
Miyagawa et al also compared the reactivity of coronary arteries in primates pretreated with
estradiol combined with either progesterone or MPA. None of the animals treated with bioidentical
progesterone experienced vasospasm, while all of those treated with MPA showed significant
vasospasm.
151
Mishra et al
150
also found that progesterone protected against coronary
hyperreactivity, while MPA had the opposite effect and induced coronary constriction.
In a blinded, randomized, crossover study, the effects of estrogen and progesterone were
compared with estrogen and MPA on exercise-induced myocardial ischemia in postmenopausal
women with coronary artery disease. Women were treated with estradiol for 4 weeks and then
randomized to receive either progesterone or MPA along with estradiol. After 10 days on the
combined treatment, the patients underwent a treadmill test. Patients were then crossed over to
the opposite treatment, and the treadmill exercise was repeated. Exercise time to myocardial

ischemia was significantly increased in the progesterone group compared with the MPA group (P
< 0.001).
162
Adams et al
152, 175
examined the cardioprotective effects of CEE and progesterone versus CEE
and MPA in primates fed atherogenic diets for 30 months. The CEE and progesterone
combination resulted in a 50% reduction in atherosclerotic plaques in the coronary arteries (P <
0.05).
175
This result was independent of changes in lipid concentrations. However, when MPA
was combined with the CEE, almost all the cardioprotective effect (atherosclerotic plaque
reduction) was reversed (P < 0.05).
152
Other studies have shown that progesterone by itself,
167,
177, 181
or in combination with estrogen,
152, 175, 177
inhibits atherosclerotic plaque formation.
Synthetic progestins, in contrast, have a completely opposite effect: they promote atherosclerotic
plaque formation and prevent the plaque-inhibiting and lipid-lowering actions of estrogen.
152, 164,
166
Transdermal estradiol, when given with or without oral progesterone, has no detrimental effects
on coagulation and no observed increased risk for venous thromboembolism (VTE).
161, 182-184
This
result is in contrast to an increased risk for VTE with CEE, with or without synthetic progestin,
which significantly increases the risk for VTE, whether both are given orally (eg, oral estrogen and
oral synthetic progestin),
71, 73, 160, 171
as transdermal estrogen and oral synthetic progestin,
161
or
both estrogen and synthetic progestin given transdermally.
185, 186
Canonico et al compared the
risk for VTE with different forms of HRT in 271 cases and 610 controls. They found that
transdermal estradiol and oral progesterone or pregnane derivatives (progestins derived from
progesterone) were not associated with VTE risk (RR = 0.7; 95% CI: 0.3–1.9 and RR = 0.9; 95%
CI: 0.4–2.3, respectively). In contrast, the use of nonpregnane derivatives increased VTE risk 4-
fold (RR = 3.9; 95% CI: 1.5–10).
161
Medroxyprogesterone acetate also has undesirable intrinsic glucocorticoid activity,
187, 188
whereas
progesterone does not have such negative effects and is a competitive inhibitor of aldosterone,
which is generally a desirable effect.
189
No changes in blood pressure are observed with
progesterone in normotensive postmenopausal women, but a slight reduction in blood pressure is
shown in hypertensive women.
190, 191
Synthetic progestins can significantly increase insulin
resistance,
167-170, 191
when compared with estrogen and progesterone.
169, 170, 191
The expression of vascular cell adhesion molecule-1 (VCAM-1) is one of the earliest events in the
atherogenic process. Otsuki et al compared the effects of progesterone and MPA on VCAM-1
expression and found that progesterone inhibited VCAM-1. No such effect was observed with
MPA (P < 0.001).
165
Discussion
Physicians must translate both basic science results and clinical outcomes to decide on the
safest, most efficacious treatment for patients. Evidence-based medicine involves the synthesis
of all available data when comparing therapeutic options for patients. Evidence-based medicine
does not mean that data should be ignored until a randomized control trial of a particular size and
duration is completed. Rather, it demands an assessment of the current available data to decide
which therapies are likely to carry the greatest benefits and the lowest risks for patients.
Progesterone, compared with MPA, is associated with greater efficacy, patient satisfaction, and
quality of life. More importantly, molecular differences between synthetic progestins and
progesterone result in differences in their pharmacological effects on breast tissue. Some of the
procarcinogenic effects of synthetic progestins contrast with the anticarcinogenic properties of
progesterone, which result in disparate clinical effects on the risk of breast cancer. Progesterone
has an antiproliferative, antiestrogenic effect on both the endometrium and breast tissue, while
synthetic progestins have antiproliferative, antiestrogenic effects on endometrial tissue, but often
have a proliferative estrogenic effect on breast tissue. Synthetic progestins show increased
estrogen-induced breast tissue proliferation and a risk for breast cancer, whereas progesterone
inhibits breast tissue proliferation and reduces the risk for breast cancer.

Until recently, estriol was available in the United States as a compounded prescription, but was
banned in January 2008 by the FDA, which stated that it was a new, unapproved drug with
unknown safety and effectiveness, although its symptomatic efficacy is generally not in
question.
192-196
The FDA has not received a single report of an adverse event in more than 30
years of estriol use. Estriol is also the subject of a US Pharmacopeia monograph. The FDA
Modernization Act of 1997 clearly indicated that drugs with a US Pharmacopeia monograph could
be compounded. It appears that the FDA took action, not because estriol is at least as safe and
effective as current estrogens on the market, but in response to what was considered
unsupported claims that estriol was safer than current forms of estrogen replacement and
because there is no standardized dose. Estriol has unique physiologic properties associated with
a reduction in the risk of breast cancer, and combining estriol with estradiol in hormone
replacement preparations would be expected to decrease the risk for breast cancer.
In cardiovascular disease, synthetic progestins, as opposed to progesterone, negate the
beneficial lipid and vascular effects of estrogen. Transdermal bioidentical estrogen and
progesterone are associated with beneficial cardiovascular and metabolic effects compared with
the use of CEE and synthetic progestins.
Based on both physiological results and clinical outcomes, current evidence demonstrates that
bioidentical hormones are associated with lower risks than their nonbioidentical counterparts.
Until there is evidence to the contrary, current evidence dictates that bioidentical hormones are
the preferred method of HRT.
Conclusion
A thorough review of the medical literature supports the claim that bioidentical hormones have
some distinctly different, often opposite, physiological effects to those of their synthetic
counterparts. With respect to the risk for breast cancer, heart disease, heart attack, and stroke,
substantial scientific and medical evidence demonstrates that bioidentical hormones are safer
and more efficacious forms of HRT than commonly used synthetic versions. More randomized
control trials of substantial size and length will be needed to further delineate these differences.
Acknowledgments
The author wishes to thank Duaine Jackola, PhD, of ScienceDocs for his editing contribution.
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Kent Holtorf, MD, Holtorf Medical Group, Inc., 23456 Hawthorne Blvd., Suite 160, Torrance, CA
90505. Tel: 310-375-2705 Fax: 310-375-2701 E-mail: kholtorf@cox.net