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

E-mail: kholtorf@cox.net

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

Kent Holtorf

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,

© 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

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

© 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:

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 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

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 (_ 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

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, 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

arrest.106,112–117

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

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

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

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

(_ 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

© 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.

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.

 

 

 

Conflict of Interest Statement

Kent Holtorf, MD discloses no conflicts of interest.

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

The Bioidentical Hormone Debate

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http://news.prnewswire.com/ 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

cancer

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

attack.

“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

http://news.prnewswire.com/ 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

counterparts.

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 www.HoltorfMed.com.

SOURCE The Holtorf Medical Group

http://news.prnewswire.com/ViewContent.aspx?ACCT=109&STORY=/www/story

/02-23-2009/0004976841&EDATE=

 

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.

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