The Bioidentical Hormone Debate

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


Kent Holtorf, MD1

1Holtorf Medical Group, Inc.,

Torrance, CA

Correspondence: Kent Holtorf, MD,

Holtorf Medical Group, Inc.,

23456 Hawthorne Blvd., Suite 160,

Torrance, CA 90505.

Tel: 310-375-2705

Fax: 310-375-2701


© Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260

Kent Holtorf


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.






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.”


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.


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,

© Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 3

The Bioidentical Hormone Debate

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 (_ 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

(_ 0.003) and increased breast tenderness (_ 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

D121 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


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

© Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260

Kent Holtorf

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:


Risk for Breast Cancer with Bioidentical


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 trials58,59 and randomized placebo

control primate trials16 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


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 (_ 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 (_ 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 (_ 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 (_ 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 (_ 0.009)

and ductal (_ 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, _ 0.007 and 4.3-fold increase, _ 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%

(_ 0.05), but progesterone decreased cell proliferation rates

by 400% (_ 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 (_ 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 Women with

low progesterone have significantly worse breast cancer

survival rates than those with more optimal progesterone


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, 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, _ 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, 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, 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-β).106–111 Estrogen receptor-α promotes

breast cell proliferation, while ER-β inhibits proliferation

and prevents breast cancer development via G2 cell cycle


Estradiol equally activates ER-α and ER-β, while estrone

selectively activates ER-α at a ratio of 5:1.118,119 In contrast,                      It is extremely important to

estriol selectively binds ER-β at a ratio of 3:1.118,119 This                           understand this concept with

unique property of estriol, in contrast to the selective ER-α                            ER-α and ER-β

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-β receptors.114 Whether this activity

is unique to CEE is unclear, but it could potentially increase

carcinogenic properties.

Furthermore, synthetic progestins synergistically downregulate

ER-β 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-β, 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


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

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)  (Prempro®) 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)

(_ 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 _g 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 (_ 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; _ 0.01), as did those receiving MPA

(8% and 17%, respectively; _ 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 (_ 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 al150 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 (_ 0.001).162

Adams et al152,175 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 (_ 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 (_ 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


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


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

(_ 0.001).165


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

© Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 Kent Holtorf


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.


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.


The author wishes to thank Duaine Jackola, PhD, of

ScienceDocs for his editing contribution.




Conflict of Interest Statement

Kent Holtorf, MD discloses no conflicts of interest.


1. The Endocrine Society. Bioidentical Hormones Position Statement,

October 2006.

© Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 9

The Bioidentical Hormone Debate

BH_Position_Statement_final_10_25_06_w_Header.pdf. Accessed

January 21, 2008.

2. Fitzpatrick LA, Pace C, Witta B. Comparison of regimens containing

oral micronized progesterone of medroxyprogesterone acetate on quality

of life in postmenopausal women: a cross-sectional survey. J Womens

Health Gend Based Med. 2000;9(4):381–387.

3. Cummings JA, Brizendine L. Comparison of physical and emotional

side effects of progesterone or medroxyprogesterone in early postmenopausal

women. Menopause. 2002;9:253–263.

4. Lindenfeld EA, Langer RD. Bleeding patterns of the hormone replacement

therapies in the postmenopausal estrogen and progestin interventions

trial. Obstet Gynecol. 2002;100(5 pt 1):853–863.

5. Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and

side effects of postmenopausal hormones: results from the Postmenopausal

Estrogen/Progestin Interventions Trial. Obstet Gynecol.


6. Hargrove JT, Maxon WS, Wentz AC, Burnett LS. Menopausal hormone

replacement therapy with continuous daily oral mircronized progesterone.

Obstet Gynecol. 1989;73(4):606–612.

7. de Lignières B. Effects of progestogens on the postmenopausal breast.

Climacteric. 2002;5(3):229–235.

8. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins

and progesterone in hormone replacement therapy and the risk

of breast cancer. J Steroid Biochem Mol Biol. 2005;96(2):95–108.

9. Ory K, Lebeau J, Levalois C, et al. Apoptosis inhibition mediated by

medroxyprogesterone acetate treatment of breast cancer cell lines.

Breast Cancer Res Treat. 2001;68(3):187–198.

10. Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ.

Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone

acetate is associated with increased epithelial proliferation

in the normal postmenopausal breast. J Clin Endocrinol Metab.


11. Jeng MH, Parker CJ, Jordan VC. Estrogenic potential of progestins in

oral contraceptives to stimulate human breast cancer cell proliferation.

Cancer Res. 1992;52(23):6539–6546.

12. Kalkhoven E, Kwakkenbos-Isbrücker L, de Laat SW, van der Saag PT,

van der Burg B. Synthetic progestins induce proliferation of breast

tumor cell lines via the progesterone or estrogen receptor. Mol Cell

Endocrinol. 1994;102(1–2):45–52.

13. Papa V, Reese CC, Brunetti A, Vigneri R, Siiteri PK, Goldfine

ID. Progestins increase insulin receptor content and insulin stimulation

of growth in human breast carcinoma cells. Cancer Res.


14. Hissom JR, Moore MR. Progestin effects on growth in the human breast

cancer cell line T-47D—possible therapeutic implications. Biochem

Biophys Res Commun. 1987;145(2):706–711.

15. Catherino WH, Jeng MH, Jordan VC. Norgestrel and gestodene stimulate

breast cancer cell growth through an oestrogen receptor mediated

mechanism. Br J Cancer. 1993;67(5):945–952.

16. Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Cline JM. Effects

of estradiol with micronized progesterone or medroxyprogesterone

acetate on risk markers for breast cancer in postmenopausal monkeys.

Breast Cancer Res Treat. 2007;101(2):125–134.

17. Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B.

Effects of conjugated estrogens, medroxyprogesterone acetate, and

tamoxifen on the mammary glands of macaques. Breast Cancer Res

Treat. 1998;48(3):221–229.

18. Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B.

Effects of hormone replacement therapy on the mammary gland of

surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol.

1996;174(1 pt 1):93–100.

19. Braunsberg H, Coldham NG, Wong W. Hormonal therapies for

breast cancer: can progestogens stimulate growth? Cancer Lett.


20. van der Burg B, Kalkhoven E, Isbrücker L, de Laat SW. Effects of

progestins on the proliferation of estrogen-dependent human breast

cancer cells under growth factor-defined conditions. J Steroid Biochem

Mol Biol. 1992;42(5):457–465.

21. Saitoh M, Ohmichi M, Takahashi K, et al. Medroxyprogesterone acetate

induces cell proliferation through up-regulation of cyclin D1 expression

via phosphatidylinositol 3-kinase/Akt/nuclear factor-kappaB cascade in

human breast cancer cells. Endocrinology. 2005;146(11):4917–4925.

22. Chang KJ, Lee TY, Linares-Cruz G, Fournier S, de Ligniéres B.

Influences of percutaneous administration of estradiol and progesterone

on human breast epithelial cell cycle in vivo. Fertil Steril.


23. Foidart JM, Colin C, Denoo X, et al. Estradiol and progesterone

regulate the proliferation of human breast epithelial cells. Fertil Steril.


24. Mueck AO, Seeger H, Wallwiener D. Comparison of proliferative

effects of estradiol and conjugated equine estrogens on human breast

cancer cells and impact of continuous combined progestogen addition.

Climacteric. 2003;6(3):221–227.

25. Inoh A, Kamiya K, Fujii Y, Yokoro K. Protective effects of progesterone

and tamoxifen in estrogen induced mammary carcinogenesis in

ovariectomized W/Fu rats. Jpn J Cancer Res. 1985;76(8):699–704.

26. Barrat J, de Lignieres B, Marpeau L, et al. Effect in vivo de

l’adminstration locale de progesterone sur l’activite mitotique des

glaactorphores humains. [The in vivo effect of the local administration

of progesterone on the mitotic activity of human ductal breast

tissue. Results of a pilot study.] J Gynecol Obstet Biol Reprod (Paris).


27. Malet C, Spritzer P, Guillaumin D, Kuttenn F. Progesterone effect on

cell growth, ultrastructural aspect and estradiol receptors of normal

breast epithelial (HBE) cells in culture. J Steroid Biochem Mol Biol.


28. Mauvais-Jarvis P, Kuttenn F, Gompel A. Antiestrogen action of progesterone

in breast tissue. Breast Cancer Res Treat. 1986;8(3):179–188.

29. Soderqvist G, von Schoultz B, Tani E, Skoog L. Estrogen and

progesterone receptor content in breast epithelial cells from

healthy women during the menstrual cycle. Am J Obstet Gynecol.

1993;168(3 pt 1):874–879.

30. Formby B, Wiley TS. Progesterone inhibits growth and induces apoptosis

in breast cancer cells: inverse effects on Bcl-2 and p53. Ann Clin

Lab Sci. 1998;28(6):360–369.

31. Formby B, Wiley TS. Bcl-2, survivin and variant CD44 v7–v10 are

downregulated and p53 is upregulated in breast cancer cells by progesterone:

inhibition of cell growth and induction of apoptosis. Mol Cell

Biochem. 1999;202(1–2):53–61.

32. Groshong SD, Owen GI, Grimison B, et al. Biphasic regulation

of breast cancer cell growth by progesterone: role of the cyclindependent

kinase inhibitors, p21 and p27(Kip1). Mol Endocrinol.


33. Segaloff A. Inhibition by progesterone of radiation-estrogen-induced

mammary cancer in the rat. Cancer Res. 1973;33(5):1136–1137.

34. Schmidt M, Renner C, Löffler G. Progesterone inhibits glucocorticoiddependent

aromatase induction in human adipose fibroblasts. J Endocrinol.


35. Jordan VC, Jeng MH, Catherino WH, Parker CJ. The estrogenic

activity of synthetic progestins used in oral contraceptives. Cancer.

1993;71(4 suppl):1501–1505.

36. Botella J, Duranti E, Viader V, Duc I, Delansorne R, Paris J. Lack of estrogenic

potential of progesterone- or 19-nor-progesterone-derived progestins

as opposed to testosterone or 19-nor-testosteorne derivatives on endometrial

Ishikawa cells. J Steroid Biochem Mol Biol. 1995;55(1):77–84.

37. Botella J, Duc I, Delansorne R, Paris J, Lahlou B. Regulation of rat uterine

steroid receptors by nomegestrol acetate, a new 19-nor-progesterone

derivative. J Pharmacol Exp Ther. 1989;248(2):758–761.

38. Markiewicz L, Hochberg RB, Gurpide E. Intrinsic estrogenicity of some

progestogenic drugs. J Steroid Biochem Mol Biol. 1992;41(1):53–58.

39. Rabe T, Bohlmann MK, Rehberger-Schneider S, Prifti S. Induction

of estrogen receptor-alpha and -beta activities by synthetic progestins.

Gynecol Endocrinol. 2000;14(2):118–126.

10 © Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260

Kent Holtorf

40. Campagnoli C, Abba C, Ambroggio S, Peris C. Pregnancy, progesterone

and progestins in relation to breast cancer risk. J Steroid Biochem Mol

Biol. 2005;97(5):441–450.

41. Seeger H, Mueck AO, Lippert TH. Effect of norethisterone acetate on

estrogen metabolism in postmenopausal women. Horm Metab Res.


42. Coldham NG, James VH. A possible mechanism for increased

breast cell proliferation by progestins through increased reductive

17 beta-hydroxysteroid dehydrogenase activity. Int J Cancer.


43. Xu B, Kitawaki J, Koshiba H, et al. Differential effects of progestogens,

by type and regimen, on estrogen-metabolizing enzymes in human breast

cancer cells. Maturitas. 2007;56(2):142–152.

44. Prost-Avallet O, Oursin J, Adessi GL. In vitro effect of synthetic

progestogens on estrone sulfatase activity in human breast carcinoma.

J Steroid Biochem Mol Biol. 1991;39(6):967–973.

45. Pasqualini JR. Differential effects of progestins on breast tissue

enzymes. Maturitas. 2003;46:45–54.

46. Pollow K, Boquoi E, Baumann J, Schmidt-Gollwitzer M, Pollow B.

Comparison of the in vitro conversion of estradiol-17 beta to estrone

of normal and neoplastic human breast. Mol Cell Endocrinol.


47. Fournier S, Kuttenn F, de Cicco F, Baudot N, Malet C, Mauvais-Jarvis P.

Estradiol 17 beta-hydroxysteroid dehydrogenase activity in human

breast fibroadenomas. J Clin Endo Metab. 1982;55(3):428–433.

48. Giangrande PH, Kimbrel EA, Edwards DP, McDonnell DP. The

opposing transcriptional activities of the two isoforms of the human

progesterone receptor are due to differential cofactor binding. Mol Cell

Biol. 2000;20(9):3102–3115.

49. Wei LL, Gonzalez-Aller C, Wood WM, Miller LA, Horwitz KB.

5’-Heterogeneity in human progesterone receptor transcripts predicts

a new amino-terminal truncated “C”-receptor and unique A-receptor

messages. Mol Endocrinol. 1990;4(12):1833–1840.

50. Mote PA, Bartow S, Tran N, Clarke CL. Loss of co-ordinate expression

of progesterone receptors A and B is an early event in breast carcinogenesis.

Breast Cancer Res Treat. 2002;72(2):163–172.

51. Graham JD, Clarke C. Expression and transcriptional activity of

progesterone receptor A and progesterone receptor B in mammalian

cells. Breast Cancer Res. 2002;4(5):187–190.

52. Kastner P, Krust A, Turcotte B, et al. Two distinct estrogen-regulated

promoters generate transcripts encoding the two functionally

different human progesterone receptor forms A and B. EMBO J.


53. Mote P, Clarke C. Relative expression of progesterone receptors

A and B in premalignant and invasive breast lesions. Breast Cancer

Res. 2000;2(suppl 1):P2.01.

54. Hopp TA, Weiss HL, Hilsenbeck SG, et al. Breast cancer patients

with progesterone receptor PR-A-rich tumors have poorer disease-free

survival rates. Clin Cancer Res. 2004;10(8):2751–2760.

55. Isaksson E, Wang H, Sahlin L, von Schoultz B, Cline JM, von Schoultz

E. Effects of long-term HRT and tamoxifen on the expression of

progesterone receptors A and B in breast tissue form surgically

postmenopausal cynomolgus macaques. Breast Cancer Res Treat.


56. Vereide AB, Kaino T, Sager G, Arnes M, Ørbo A. Effect of levonorgestrel

IUD and oral medroxyprogesterone acetate on glandular and

stromal progesterone receptors (PRA and PRB), and estrogen receptors

(ER-alpha and ER-beta) in human endometrial hyperplasia. Gynecol

Oncol. 2006;101(2):214–223.

57. Custodia-Lora N, Novillo A, Callard IP. Regulation of hepatic

progesterone and estrogen receptors in the female turtle, Chrysemys

picta: relationship to vitellogenesis. Gen Comp Endocrinol.


58. Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast

cancer risk in relation to different types of hormone replacement therapy

in the E3N-EPIC cohort. Int J Cancer. 2005;114:448–454.

59. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer

associated with different hormone replacement therapies: results from the

E3N cohort study. Breast Cancer Res Treat. 2008;107(1):103–111.

60. Peck JD, Hulka BS, Poole C, Savitz DA, Baird D, Richardson BE.

Steroid hormone levels during pregnancy and incidence of maternal

breast cancer. Cancer Epidemiol Biomarkers Prev. 2002;11(4):361–


61. Micheli A, Muti P, Secreto G, et al. Endogenous sex hormones and

subsequent breast cancer in premenopausal women. Int J Cancer.


62. Gottardis M, Ertürk E, Rose DP. Effects of progesterone administration

on N-nitrosomethylurea-induced rat mammary carcinogenesis. Eur J

Cancer Clin Oncol. 1983;19(10):1479–1484.

63. Grubbs CJ, Farnell DR, Hill DL, McDonough KC. Chemoprevention

of N-nitroso-N-methylurea induced mammary cancers by pretreatment

with 17 beta-estradiol and progesterone. J Natl Cancer Inst.


64. Kledzik GS, Bradley CJ, Meites J. Reduction of carcinogen-induced

mammary cancer incidence in rats by early treatment with hormones

or drugs. Cancer Res, 1974;34(11):2953–2956.

65. Welsch CH, Clemens JA, Meites J. Effects of multiple pituitary

homografts or progesterone on 7,12-dimethylbenz[a]anthracene-

induced mammary tumors in rats. J Natl Cancer Inst.


66. Bernstein L, Yuan JM, Ross RK, et al. Serum hormone levels in

pre-menopausal Chinese women in Shanghai and white women in Los

Angeles: results from two breast cancer case-control studies. Cancer

Causes Control. 1990;1(1):51–58.

67. Drafta D, Schindler AE, Milcu SM, et al. Plasma hormones

in pre- and postmenopausal breast cancer. J Steroid Biochem.


68. Malarkey WB, Schroeder LL, Stevens VC, James AG, Lanese RR.

Twenty-four-hour preoperative endocrine profiles in women with benign

and malignant breast disease. Cancer Res. 1977;37(12):4655–4659.

69. Meyer F, Brown JB, Morrison AS, MacMahon B. Endogenous sex

hormones, prolactin, and breast cancer in premenopausal women. J Natl

Cancer Inst. 1986;77(3):613–616.

70. Secreto G, Toniolo P, Berrino F, et al. Increased androgenic activity and

breast cancer risk in premenopausal women. Cancer Res. 1984(12 pt 1);


71. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the

Women’s Health Initiative Investigators. Risks and benefits of estrogen

plus progestin in healthy postmenopausal women: principal results

From the Women’s Health Initiative randomized controlled trial. JAMA.


72. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated

equine estrogen in postmenopausal women with hysterectomy:

the Women’s Health Initiative randomized controlled trial. JAMA.


73. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen

plus progestin on breast cancer and mammography in healthy postmenopausal

women: the Women’s Health Initiative Randomized Trial.

JAMA. 2003;289(24):3243–3253.

74. Porch JV, Lee IM, Cook NR, Rexrode KM, Burin JE. Estrogen-progestin

replacement therapy and breast cancer risk: the Women’s Health Study

(United States). Cancer Causes Control. 2002;13(9):847–854.

75. Lee SA, Ross RK, Pike MC. An overview of menopausal oestrogenprogestin

hormone therapy and breast cancer risk. Br J Cancer.


76. Ewertz M, Mellemkjaer L, Poulsen AH, et al. Hormone use for

menopausal symptoms and risk of breast cancer. A Danish cohort study.

Br J Cancer. 2005;92(7):1293–1297.

77. Newcomb PA, Titus-Ernstoff L, Egan KM, et al. Postmenopausal

estrogen and progestin use in relation to breast cancer risk. Cancer

Epid Bio Prev. 2002;11(7):593–600.

© Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 11

The Bioidentical Hormone Debate

78. Stahlberg C, Pedersen AT, Lynge E, et al. Increased risk of breast

cancer following different regimens of hormone replacement therapy

frequently used in Europe. Int J Cancer. 2004;109(5):721–727.

79. Li CI. Postmenopausal hormone therapy and the risk of breast cancer:

the view of an epidemiologist. Maturitas. 2004;49(1):44–50.

80. Magnusson C, Baron JA, Correia N, Bergström R, Adami HO, Persson

I. Breast-cancer risk following long-term oestrogen- and oestrogenprogestin-

replacement therapy. Int J Cancer. 1999;81(3):339–344.

81. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R.

Estrogen-progestin replacement and risk of breast cancer. JAMA.


82. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone

replacement therapy on breast cancer risk: estrogen versus estrogen

plus progestin. J Natl Cancer Inst. 2000;92(4):328–332.

83. Warren MP. A comparative review of the risks and benefits of

hormone replacement therapy regimens. Am J Obstet Gynecol.


84. Weiss LK, Burkman RT, Cushing-Haugen KL, et al. Hormone replacement

therapy regimens and breast cancer risk(1). Obstet Gynecol.


85. Li CI, Malone KE, Porter PL, et al. Relationship between long durations

and different regimens of hormone therapy and risk of breast cancer.

JAMA. 2003;289(24):3254–3263.

86. Beral V; Million Women Study Collaborators. Breast cancer and

hormone-replacement therapy in the Million Women Study. Lancet.


87. Kirsh V, Kreiger N. Estrogen and estrogen–progestin replacement

therapy and risk of postmenopausal breast cancer in Canada. Cancer

Causes Control. 2002;13(6):583–590.

88. Breast cancer and hormone replacement therapy: collaborative reanalysis

of data from 51 epidemiological studies of 52,705 women with breast

cancer and 108,411 women without breast cancer. Collaborative Group

on Hormonal Factors in Breast Cancer. Lancet. 1997;350(9084):1047–


89. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal

estrogen and estrogen-progestin replacement therapy and breast

cancer risk. JAMA. 2000;283(4):485–491.

90. Colditz G, Rosner B. Use of estrogen plus progestin is associated with

greater increase in breast cancer risk than estrogen alone. Am J Epidemiol.


91. Persson I, Weiderpass E, Bergkvist L, Bergström R, Schairer C. Risks

of breast and endometrial cancer after estrogen and estrogen-progestin

replacement. Cancer Causes Control. 1999;10(4):253–260.

92. Chen CL, Weiss NS, Newcomb P, Barlow W, White E. Hormone

replacement therapy in relation to breast cancer. JAMA.


93. Pike MC, Ross RK. Progestins and menopause: epidemiological studies

of risks of endometrial and breast cancer. Steroids. 2000;65(10–11-


94. Santen RJ, Pinkerton J, McCartney C, Petroni GR. Risk of breast cancer

with progestins in combination with estrogen as hormone replacement

therapy. J Clin Endocrinol Metab. 2001;86(1):16–23.

95. Stahlberg C, Pederson AT, Lynge E, Ottesen B. Hormone replacement

therapy and risk of breast cancer: the role of progestins. Acta Obstet

Gynecol Scand. 2003;82(7):335–344.

96. Olsson HL, Ingvar C, Bladström A. Hormone replacement therapy

containing progestins and given continuously increases breast carcinoma

risk in Sweden. Cancer. 2003;97(6):1387–1392.

97. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and

progestins and the risk of breast cancer in postmenopausal women. N

Engl J Med. 1995;332(24):1589–1593.

98. Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years

according to risk factor status: data from the Nurses’ Health Study. Am

J Epidemiol. 2000;152(10):950–964.

99. Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence

in women with a history of progesterone deficiency. Am J Epidemiol.


100. Badwe RA, Wang DY, Gregory WM, et al. Serum progesterone at the

time of surgery and survival in women with premenopausal operable

breast cancer. Eur J Cancer. 1994;30A(4):445–448.

101. Mohr PE, Wang DY, Gregory WM, Richards MA, Fentiman IS. Serum

progesterone and prognosis in operable breast cancer. Br J Cancer.


102. Veronese SM, Gambacorta M. Detection of Ki-67 proliferation rate in

breast cancer. Correlation with clinical and pathologic features. Am J

Clin Pathol. 1991;95(1):30–34.

103. Innes KE, Byers TE. First pregnancy characteristics and subsequent

breast cancer risk among young women. Int J Cancer.


104. Troisi R, Weiss HA, Hoover RN, et al. Pregnancy characteristics and

maternal risk of breast cancer. Epidemiology. 1998;9(6):641–647.

105. Vatten LJ, Romundstad PR, Trichopoulos D, Skjærven R.

Pre-eclampsia in pregnancy and subsequent risk for breast cancer. Br

J Cancer. 2002;87(9):971–973.

106. Paruthiyil S, Parma H, Kerekatte V, Cunha GR, Firestone GL,

Leitman DC. Estrogen receptor beta inhibits human breast cancer cell

proliferation and tumor formation by causing a G2 cycle arrest. Cancer

Res. 2004;64(1):423–428.

107. Paech K, Webb P, Kuiper GG, et al. Differential ligand activation

of estrogen receptors ERalpha and ERbeta at AP1 sties. Science.


108. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA.

Cloning of a novel estrogen receptor expressed in rat prostate and

ovary. Proc Natl Acad Sci U S A. 1996;93(12):5925–5930.

109. Green S, Walter P, Greene G, et al. Cloning of the human oestrogen

receptor cDNA. J Steroid Biochem. 1986;24(1):77–83.

110. Katzenellenbogen BS, Montano MM, Ediger TR, et al. Estrogen

receptors: selective ligands, partners, and distinctive pharmacology.

Recent Prog Horm Res. 2000;55:163–193.

111. Nilsson S, Mäkelä S, Treuter E, et al. Mechanisms of estrogen action.

Physiol Rev. 2001;81(4):1535–1565.

112. Helguero LA, Faulds MH, Gustafsson JA, Haldosén LA. Estrogen

receptors alpha (ERalpha) and beta (ERbeta) differentially regulate

proliferation and apoptosis of the normal murine mammary epithelial

cell line HC11. Oncogene. 2005;24(44):6605–6616.

113. Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERbeta

expression as a common step in estrogen-dependent tumor progression.

Endocr Relat Cancer. 2004;11(3):537–551.

114. Isaksson E, Wang H, Sahlin L, et al. Expression of estrogen receptors

(alpha, beta) and insulin-like growth factor-1 in breast tissue form

surgically postmenopausal cynomolgus macaques after long-term

treatment with HRT and tamoxifen. Breast. 2002;11(4):295–300.

115. Weatherman RV, Clegg NJ, Scanlan TS. Differential SERM activation

of the estrogen receptors (ERalpha and ERbeta) at AP-1 sites. Chem

Biol. 2001;8(5):427–436.

116. Pettersson K, Delaunay F, Gustafsson JA. Estrogen receptor

beta acts a dominant regulator of estrogen signaling. Oncogene.


117. Saji S, Jensen EV, Nilsson S, Rylander T, Warner, Gustafsson JA.

Estrogen receptors alpha and beta in the rodent mammary gland. Proc

Natl Acad Sci U S A. 2000;97(1):337–342.

118. Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR. Quantitative structureactivity

relationship of various endogenous estrogen metabolites

for human estrogen receptor alpha and beta subtypes: Insights into

the structural determinants favoring a differential subtype binding.

Endocrinology. 2006;147(9):4132–4150.

119. Rich RL, Hoth LR, Geoghegan KF, et al. Kinetic analysis of

estrogen receptor/ligand interactions. Proc Natl Acad Sci U S A.


120. Ekena K, Katzenellenbogen JA, Katzenellenbogen BS. Determinants

of ligand specificity of estrogen receptor-alpha: estrogen versus androgen

discrimination. J Biol Chem. 1998;273(2):693–699.

12 © Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260

Kent Holtorf

121. Hanstein B, Liu H, Yancisin MC, Brown M. Functional analysis

of a novel estrogen receptor-beta isoform. Mol Endocrinol.


122. Lemon HM. Pathophysiologic considerations in the treatment of

menopausal patients with oestrogens; the role of oestriol in the prevention

of mammary carcinoma. Acta Endocrinol Suppl (Copenh).


123. Lemon HM, Kumar PF, Peterson C, Rodriguez-Sierra JF, Abbo KM.

Inhibition of radiogenic mammary carcinoma in rats by estriol or

tamoxifen. Cancer. 1989;63(9):1685–1692.

124. Lemon HM. Estriol prevention of mammary carcinoma induced

by 7,12-dimethylbenzanthracene and procarbazine. Cancer Res.


125. MacMahon B, Cole P, Brown JB, et al. Oestrogen profiles of Asian

and North American women. Lancet. 1971;2(7730):900–902.

126. Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S.

Differential response of estrogen receptor alpha and receptor beta to partial

estrogen agonists/antagonists. Mol Pharmacol. 1998;54(1):105–112.

127. Pisha E, Lui X, Constantinou AI, Bolton JL. Evidence that a metabolite

of equine estrogens, 4-hydroxequilenin, induces cellular transformation

in vitro. Chem Res Toxicol. 2001;14(1):82–90.

128. Zhang F, Chen Y, Pisha E, et al. The major metabolite of equilin,

4-hyroxyequilin, autoxidizes to an o-quinone with isomerizes to the

potent cytotoxin 4-hydroyequilenin-o-quinone. Chem Res Toxicol.


129. Chen Y, Liu X, Pisha E, et al. A metabolite of equine estrogens,

4-hydroxyequilenin, induces DNA damage and apop tosis in breast

cancer cell lines. Chem Res Toxicol. 2000;13(5):342–350.

130. Zhang F, Swanson SM, van Breemen RB, et al. Equine estrogen metabolite

4-hydroxyequilenin induces DNA damage in the rat mammary

tissues: formation of single-strand breaks, apurinic sites, stable adducts,

and oxidized bases. Chem Res Toxicol. 2001;14(12):1654–1659.

131. Shen L, Qiu S, Chen Y, et al. Alkylation of 2’-deoxynucleosides and

DNA by the Premarin metabolite 4-hydroxyequilenin semiquinone

radical. Chem Res Toxicol. 1998;11(2):94–101.

132. Gross J, Modan B, Bertini B, et al. Relationship between steroid excretion

patterns and breast cancer incidence in Israeli women of various

origins. J Natl Cancer Inst. 1997;59(1):7–11.

133. Cole P, MacMahon B. Oestrogen fractions during early reproductive life

in the aetiology of breast cancer. Lancet. 1969;1(7595):604–606.

134. Dickinson LE, MacMahon B, Cole P, Brown JB. Estrogen profiles

of Oriental and Caucasian women in Hawaii. N Engl J Med.


135. Melamed M, Castaño E, Notides AC, Sasson S. Molecular and

kinetic basis for the mixed agonist/antagonist activity of estriol. Mol

Endocrinol. 1997;11(12):1868–1878.

136. Speroff L. The breast as an endocrine target organ. Contemp Obstet

Gynec. 1977;9:69–72.

137. Rosner B, Colditz, GA, Willett WC. Reproductive risk factors in a

prospective study of breast cancer: the Nurses’ Health Study. Am J

Epidemiol. 1994;139(8):819–835.

138. Russo J, Tay LK, Russo IH. Differentiation of the mammary gland

and susceptibility to carcinogenesis. Breast Cancer Res Treat.


139. Pasqualini JR. The fetus, pregnancy, and breast cancer. In:

Pasqualini JR, ed. Breast Cancer: Prognosis, Treatment, and Prevention.

New York, NY: Marcel Dekker Inc; 2002:19–71.

140. Vatten LJ, Romundstad PR, Trichopoulos D, Skjærven R. Pregnancy

related protection against breast cancer depends on length of gestation.

Br J Cancer. 2002;87(3):289–290.

141. Ekbom A, Hsieh CC, Lipworth L, Adami HQ, Trichopoulos D. Intrauterine

environment and breast cancer risk in women: a populationbased

study. J Natl Cancer Inst. 1997;89(1):71–76.

142. Ursin G, Wilson M, Henderson BE, et al. Do urinary estrogen metabolites

reflect the differences in breast cancer risk between Singapore

Chinese and United States African-American and white women?

Cancer Res. 2001;61(8):3326–3329.

143. Lemon HM. Genetic predisposition to carcinoma of the breast: multiple

human genotypes for estrogen 16 alpha hydroxylase activity in Caucasians.

J Surg Oncol. 1972;4(3):255–273.

144. Bakken K, Alsaker E, Eggen AE, Lund E. Hormone replacement

therapy and incidence of hormone-dependent cancers in the Norwegian

Women and Cancer study. Int J Cancer. 2004;112(1):130–134.

145. Lippman M, Monaco ME, Bolan G. Effects of estrone, estradiol, and

estriol on hormone-responsive human breast cancer in long-term tissue

culture. Cancer Res. 1977;37(6):1901–1907.

146. Lemon HM, Wotiz HH, Parsons L, Mozden PJ. Reduced estriol

excretion in patients with breast cancer prior to endocrine therapy.

JAMA. 1966;196(13):1128–136.

147. Marmorston J, Fowley LG, Myers SM, Stern E, Hopkins CE. II. Urinary

excretion of estrone, estradiol and estriol by patients with breast cancer

and benign breast disease. Am J Obstet Gynecol. 1965;92:460–467.

148. Ottosson UB, Johansson BG, von Schoultz B. Subfractions of

high-density lipoprotein cholesterol during estrogen replacement

therapy: a comparison between progestogens and natural progesterone.

Am J Obstet Gynecol. 1985;151(6):746–750.

149. Minshall RD, Stanczyk FZ, Miyagawa K, et al. Ovarian steroid protection

against coronary artery hyperreactivity in rhesus monkeys. J Clin

Endocrinol Metab. 1998;83(2):649–659.

150. Mishra RG, Hermsmeyer RK, Miyagawas K, et al. Medroxyprogesterone

acetate and dihydrotestosterone induce coronary

hyperreactivity in intact male rhesus monkeys. J Clin Endocrinol

Metab. 2005;90(6):3706–3714.

151. Miyagawa K, Roöch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone

interferes with ovarian steroid protection against coronary

vasospasm. Nat Med. 1997;3(3):324–327.

152. Adams MR, Register TC, Golden DL, Wagner JD, Williams J.

Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated

equine estrogens on coronary artery atherosclerosis. Arterioscler

Thromb Vasc Biol. 1997;17(1):217–221.

153. Saarikoski S, Yliskoski M, Penttilä I. Sequential use of norethisterone

and natural progesterone in pre-menopausal bleeding disorders.

Maturitas. 1990;12(2):89–97.

154. Effects of estrogen or estrogen/progestin regimens on heart disease

risk factors in postmenopausal women. The Postmenopausal Estrogen/

Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI

Trial. JAMA. 1995;273(3):199–208.

155. Fåhraeus L, Larsson-Cohn U, Wallentin L. L-norgestrel and progesterone

have different influences on plasma lipoproteins. Eur J Clin

Invest. 1983;13(6):447–453.

156. Larsson-Cohn U, Fåhraeus L, Wallentin L, Zador G. Lipoprotein

changes may be minimized by proper composition of a combined oral

contraceptive. Fertil Steril. 1981;35(2):172–179.

157. Ottosson UB. Oral progesterone and estrogen/progestogen therapy. Effects

of natural and synthetic hormones on subfractions of HDL cholesterol

and liver proteins. Acta Obstet Gynecol Scand Suppl. 1984;127:1–37.

158. Mälkönen M, Manninen V, Hirvonen E. Effects of danazol and

lynestrenol on serum lipoproteins in endometriosis. Clin Pharmacol

Ther. 1980;28(5):602–604.

159. Hirvonen E, Malkonen M, Manninen V. Effects of different progestogens

on lipoproteins during postmenopausal replacement therapy.

N Engl J Med. 1981;304(10):560–563.

160. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and

risk of venous thrombosis. JAMA. 2004;292(13):1573–1580.

161. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and

venous thromboembolism among postmenopausal women: impact of

the route of estrogen administration and progestogens: the ESTHER

study. Circulation. 2007;115(7):840–845.

162. Rosano GM, Webb CM, Chierchia S, et al. Natural progesterone, but

not medroxyprogesterone acetate, enhances the beneficial effect of

estrogen on exercise-induced myocardial ischemia in postmenopausal

women. J Am Coll Cardiol. 2000;36(7):2154–2159.

163. Miller VT, Muesing RA, LaRosa JC, Stoy DB, Phillips EA, Stillman RJ.

Effects of conjugated equine estrogen with and without three different

© Postgraduate Medicine, Volume 121, Issue 1, January 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 13

The Bioidentical Hormone Debate

progestogens on lipoproteins, high-density lipoprotein subfractions,

and apolipoprotein A-1. Obstet Gynecol. 1991;77(2):235–240.

164. Levine RL, Chen SJ, Durand J, Chen YF, Oparil S. Medroxyprogesterone

attenuates estrogen-mediated inhibition of neointima

formation after balloon injury of the rat carotid artery. Circulation.


165. Otsuki M, Saito H, Xu X, et al. Progesterone, but not medroxyprogesterone,

inhibits vascular cell adhesion molecule-1 expression in

human vascular endothelial cells. Arterioscler Thromb Vasc Biol.


166. Register TC, Adams MR, Golden DL, Clarkson TB. Conjugated equine

estrogens alone, but not in combination with medroxyprogesterone

acetate, inhibit aortic connective tissue remodeling after plasma

lipid lowering in female monkeys. Arterioscler Thromb Vasc Biol.


167. Wagner JD, Martino MA, Jayo MJ, Anthony MS, Clarkson TB,

Cefalu WT. The effects of hormone replacement therapy on carbohydrate

metabolism and cardiovascular risk factors in surgically postmenopausal

cynomolgus monkeys. Metabolism. 1996;45(10):1254–1262.

168. Lindheim SR, Presser SC, Ditkoff EC, Vijod MA, Stanczyk FZ,

Lobo RA. A possible bimodal effect of estrogen on insulin sensitivity in

postmenopausal women and the attenuating effect of added progestin.

Fertil Steril. 1993;60(4):664–667.

169. Spencer CP, Godsland IF, Cooper AJ, Ross D, Whitehead MI,

Stevenson JC. Effects of oral and transdermal 17_-estradiol with

cyclical oral norethindrone acetate on insulin sensitivity, secretion,

and elimination in postmenopausal women. Metabolism.


170. Godsland IF, Gangar K, Walton C, et al. Insulin resistance,

secretion, and elimination in postmenopausal women receiving

oral or transdermal hormone replacement therapy. Metabolism.


171. Feeman WE Jr. Thrombotic stroke in an otherwise healthy middleaged

female related to the use of continuous-combined conjugated

equine estrogens and medroxyprogesterone acetate. J Gend Specif

Med. 2000;3(8):62–64.

172. Jeanes HL, Wanikiat P, Sharif I, Gray GA. Medroxyprogesterone

acetate inhibits the cardioprotective effect of estrogen in experimental

ischemia-reperfusion injury. Menopause. 2006;13(1):80–86.

173. Jensen J, Riis BJ, Strøm V, Nilas L, Christiansen C. Long-term

effects of percutaneous estrogens and oral progesterone on serum

lipoproteins in postmenopausal women. Am J Obstet Gynecol.


174. Williams JK, Honoré EK, Washburn SA, Clarkson TB. Effects of

hormone replacement on therapy on reactivity of atherosclerotic

coronary arteries in cynomolgus monkeys. J Am Coll Cardiol.


175. Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary

artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys.

Lack of an effect of added progesterone. Arteriosclerosis.


176. Bolaji II, Grimes H, Mortimer G, Tallon DF, Fottrell PF, O’Dwyer

EM. Low-dose progesterone therapy in oestrogenised postmenopausal

women: effects on plasma lipids, lipoproteins and liver function

parameters. Eur J Obstet Gynecol Reprod Biol. 1993;48(1):61–68.

177. Morey AK, Pedram A, Razandi M, et al. Estrogen and progesterone

inhibit vascular smooth muscle proliferation. Endocrinology.


178. Lee WS, Harder JA, Yoshizumi M, Lee ME, Haber E. Progesterone

inhibits arterial smooth muscle cell proliferation. Nat Med.


179. Minshall RD, Miyagawa K, Chadwick CC, Novy MJ, Hermsmeyer K.

In vitro modulation of primate coronary vascular muscle cell reactivity

by ovarian steroid hormones. FASEB J. 1998;12(13):1419–1429.

180. Minshall RD, Pavcnik D, Halushka PV, Hermsmeyer RK. Progesterone

regulation of vascular thromboxane A2 receptors in rhesus monkeys.

Am J Physiol Heart Circ Physiol. 2001;281(4):H1498–H1507.

181. Houser SL, Aretz HT, Quist WC, Chang Y, Schreiber AD. Serum

lipids and arterial plaque load are altered independently with highdose

progesterone in hypercholesterolemic male rabbits. Cardiovasc

Pathol. 2000;9(6):317–322.

182. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R,

Aiach M. Effects of oral and transdermal estrogen/progesterone

regimens on blood coagulation and fibrinolysis in postmenopausal

women. A randomized controlled trial. Arterioscler Thromb Vasc Biol.


183. Martinez C, Basurto L, Zarate A, Saucedo R, Gaminio E, Collazo J.

Transdermal estradiol does not impair hemostatic biomarkers in postmenopausal

women. Maturitas. 2005;50(1):39–43.

184. Oger E, Alhenc-Gelas M, Lacut K, et al. Differential effects of oral

and transdermal estrogen/progesterone regimens on sensitivity to

activated protein C among postmenopausal women: a randomized

trial. Arterioscler Thromb Vasc Biol. 2003;23(9):1671–1676.

185. Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism,

myocardial infarction, and stroke among transdermal contraceptive

system users. Obstet Gynecol. 2007;109(2 pt 1):339–346.

186. Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous

thromboembolism in women using a contraceptive transdermal patch

and oral contraceptives contain norgestimate and 35 _g of ethinyl

estradiol. Contraception. 2006;73(3):223–228.

187. Hellman I, Yoshida K, Zumoff B, Levin J, Kream J, Fukushima DK.

The effect of medroxyprogesterone acetate on the pituitary-adrenal

axis. J Clin Endocrinol Metab. 1976;42(5):912–917.

188. Davila E, Vogel CL, East D, Cairns V, Hilsenbeck S. Clinical trial

of high-dose oral medroxyprogesteorne acetate in the treatment

of metastatic breast cancer and review of the literature. Cancer.


189. Corvol P, Elkik F, Feneant M, et al. Effect of progesterone and

progestins on water and salt metabolism. In: Bardin CW, Milgrom E,

Mauvais-Jarvis P, eds. Progesterone and Progestins. New York, NY:

Raven Press; 1983;1979–1986.

190. Rylance PB, Brincat M, Lafferty K, et al. Natural progesterone and

antihypertensive action. Bri Med J. 1985(6461);290:13–14.

191. Elkind-Hirsch KE, Sherman LD, Malinak R. Hormone replacement

therapy alters insulin sensitivity in young women with premature

ovarian failure. J Clin Endocrinol Metab. 1993;76(2):472–475.

192. Tzingounis VA, Aksu MF, Greenblatt RB. Estriol in the management

of the menopause. JAMA. 1978;239(16):1638–1641.

193. Yang TS, Tsan SH, Chang SP, Ng HT. Efficacy and safety of estriol

replacement therapy for climacteric women. Chin Med J (Taipei).


194. Perovi D, Kopajtic B, Stankovi T. Treatment of climacteric complaints

with oestriol. Arzneimittel-Forschung. 1975;25(6):962–964.

195. van der Linden MC, Gerretsen G, Brandhorst MS, Ooms EC,

Kremer CM, Doesburg WH. The effect of estriol on the cytology of

urethra and vagina in postmenopausal women with genito-urinary

symptoms. Eur J Obstet Gynecol Reprod Biol. 1993;51(1):29–33.

196. Cardoza L, Rekers H, Tapp A, et al. Oestriol in the treatment of postmenopausal

urgency: a multicentre study. Maturitas. 1993;18(1):47–53. 02-23-09 Page 1 of 2

New Analysis Finds Bioidentical Hormones Safer Than

Standard Hormone Replacement Therapy

Comprehensive review demonstrates bioidentical hormones are superior to

synthetic HRT with greater cardiovascular benefits and reduced risk of breast


TORRANCE, Calif., Feb. 23 /PRNewswire/ — The most comprehensive analysis

to date, published in the Postgraduate Medical Journal, a leading peer-reviewed

publication for practicing clinicians, showed that bioidentical hormones are

associated with reduced health risks and are more efficacious than their synthetic

counterparts. Conducted by a leading expert in hormone replacement, Kent

Holtorf, M.D., medical director of the Holtorf Medical Group in Torrance,

California, the paper reviewed and evaluated results from more than 200

physiological and clinical studies. It demonstrated that bioidentical hormone

replacement therapy is both more effective and has greater health benefits for

women suffering with symptoms of menopause than hormone replacement

therapy with synthetic hormones. Synthetic forms of hormone replacement

therapy prescribe substances such as Premarin, Provera and Prempro and

present real health risks with increased risks of breast cancer, stroke and heart


“Many physicians and so-called experts state that there is no evidence that

bioidentical hormones are safer than synthetic HRT. A thorough review of the

medical literature, however, clearly supports the claim that bioidentical hormones

have some distinctly different, often opposite, physiological effects to those of

their synthetic hormones,” said Dr. Holtorf, whose practice treats more than

7,000 patients each year. “The medical literature demonstrates that bioidentical

hormone replacement therapy is highly effective and carries a reduced, rather

than an increased risk of breast cancer and cardiovascular disease.”

The review also showed that patients undergoing bioidentical HRT were less

likely to experience sleep problems, anxiety, depression and cognitive effects –

common side effects of synthetic hormones and are associated with a reduced

risk for breast cancer and superior cardiovascular protection.

“While larger, randomized clinical studies are needed, the review of current

medical literature demonstrates that bioidentical hormones are a safer, highly

effective option for women, and any physician that is practicing evidence-based 02-23-09 Page 2 of 2

medicine should be using bioidentical hormone replacement for their patients,”

said Dr. Holtorf.

Synthetic HRT preparations, which are the most commonly prescribed method of

HRT in the United States, are comprised of pregnant horse hormones that are

not found in the human body or synthetic hormones that have physiologic effects

that mimic or mirror the natural estrogen or progesterone effects in the body. In

contrast, bioidentical hormone replacement contains molecules that are exact

replicas of the endogenous estrogens and progesterone found in the body and,

as such, have distinctly different physiological effects than their synthetic


The Holtorf Medical Group is one of the leading authorities on hormone

replacement and has been educating patients on the superiority and safety of

natural hormones versus synthetic for many years. Dr. Holtorf is available to

discuss the FDA’s move to halt the use of bioidentical hormones while promoting

synthetic hormone therapy, and why discouraging healthcare professionals from

using this treatment threatens the health of women everywhere. In addition, Dr.

Holtorf can dispel the common misconceptions associated with bioidentical

hormone treatment and discuss the significant health benefits patients can

expect from this treatment compared to synthetic versions of HRT. For more

information or for a copy of the study go to

SOURCE The Holtorf Medical Group



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.

Hormone Therapy 

Menopause and Hormonal Imbalance
The Anatomy of a Hot Flash
“Tired but Wired” - Fatigue, Stress and Hormone Imbalance
Facts On Hormone Balance Issues
Hormone Imbalance and PMS
All About Natural (Bio-identical) Hormones
What is Progesterone and Why Do We Need It?
Hormone Balance and Osteoporosis
Estrogen Dominance and Low Thyroid
Depression and Mood Swings
Hormone Imbalance and Hysterectomy
Hormone Imbalance and Insulin Resistance
Vitamin D Deficiency 
What is Adrenal Fatigue?
Saliva Testing
Bio-Identical Hormones: What You Need To Know
What is Testosterone?
What is Estrogen?
Bioidentical Hormone Abstract
The Bioidentical Hormone Debate
Bio-Identical Hormone Therapy
How To Collect Saliva