Numerous forms of estrogens and progestins are utilized for the
treatment of menopausal complaints and associated conditions that occur
temporally. Although known to be different with respect to molecular
structure, receptor affinity, metabolism, and other
physiological traits, most have been treated as if they were clinically
identical. The majority of these hormone preparations, commonly referred
to as hormone replacement therapy (HRT), should perhaps be more aptly
referred to as hormone substitution therapy, as most of the therapies
utilized do not exactly match those produced in the body.Research
indicates these synthetic hormones vary clinically in safety and
efficacy. As such,women and their physicians have, in
increasing numbers, been opting for the use of bioidentical hormones;
i.e., those that match the structure and function of hormones produced
in the body.With greater utilization and research
surrounding bioidentical hormones, the differences can now begin to be
fully assessed and appreciated. This article reviews the disparities
between synthetic and bioidentical estrogens and progestins/progesterone
with respect to safety and efficacy;special attention is devoted to
clinical outcomes in the breast, endometrium, bone,
cardiovascular system, and brain. The studies reviewed
suggest bioidentical progesterone does not have a negative effect on
blood lipids or vasculature as do many synthetic progestins, and may
carry less risk with respect to breast cancer incidence. Studies of
both bioidentical estrogens and progesterone suggest a reduced risk of
blood clots compared to nonbioidentical preparations. Bioidentical
hormone preparations have demonstrated effectiveness in addressing
menopausal symptoms. The author advocates for continued research
on bioidentical hormones and concludes there is currently sufficient
evidence to support their preferred use over that of their synthetic
cousins.(Altern Med Rev 2006;11(3):208-223)
Over the last decade, women and their physicians have in increasing
numbers been opting for the use of natural, bioidentical hormones for
treatment of symptoms of menopause and to support bone and heart health.
(1) The trend away from the use of conventional synthetic hormones,
toward those specifically matching the hormones produced in humans
(bioidentical)has been driven by several factors, including a
global trend toward everything "natural” as seen in the increased
interest in organic foods and complementary and alternative medicine
(CAM). Perhaps the most significant factor driving the increased
interest in bioidentical hormones is the rising fear or suspicion of the
"synthetic” hormones used in conventional hormone replacement therapy
(HRT). Over the last decade, research-based media reports of risks
associated with conventional HRT have prompted women’s concerns and
altered the approach to hormone use. (2,3) This has been most evident
following the results of the U.S. government-sponsored Women’s Health
Initiative (WHI) study in 2002. The WHI study results led to the
conclusion of experts in the field that the risk of using conventional
HRT (non-bioidentical hormones), specifically Premarin®and Provera®,
outweighed the benefits provided. (4) This report was followed by a
significant decline in the use of synthetic hormones at menopause, and a
growing number of women and their physicians utilizing and
advocating the use of bioidentical hormones. The question, without the
value of a similar long-term study looking at bioidentical hormones, is
whether or not the evidence exists to support their preferred use over
their synthetic cousins.
Hormone Changes Surrounding Natural (Non-induced) Menopause
Menopause is defined as the cessation of menstruation occurring as a
result of the loss of ovarian follicular activity. At birth, a woman has
a million eggs, by puberty a mere 300,000. This loss of eggs
is referred to as atresia, a natural, albeit incompletely understood,
process whereby the follicles enter an incomplete growth phase. This
process continues throughout a woman’s life. Thousands of follicles are
lost to atresia compared to one or a few lost each month to ovulation.
As a woman ages and as a result of the decreasing follicles,
follicle-stimulating hormone (FSH) levels gradually increase and the
cycle begins to shift, with a shortening of the follicular phase that
can begin as early as a woman’s 20s. (5,6) In the 10-15 years prior to
menopause, this rate of follicular atresia begins to accelerate. (7,8)
Perimenopause is the term used to describe the time of transition
between a woman’s reproductive years and cessation of menstruation.
Typically perimenopause occurs between the ages of 40 and 51 and can
last anywhere from six months to 10 years. During this time, hormone
levels fluctuate and decline naturally, although not necessarily in an
Perimenopause often begins with an alteration in cycle and bleeding
regularity due to fluctuatin ghormones, anovulatory cycles, and changes
in timing of ovulation. Cycles may be long or short, ovulatory or
anovulatory. (8) Even women who cycle regularly during perimenopause can
have significant variability in hormone levels. (7) Progesterone levels
drop with anovulatory cycles and a decline in luteal function.Estrogen
levels fluctuate in response to rising FSHlevels and provide feedback
inhibition to FSH. (6) Significant variability may occur in estradiol
and inhibin (a hormone that inhibits FSH), and gonadotropins may rise
abruptly. (5,6,9) Testosterone levels decline with age and do not appear
to change significantly with natural menopause. By menopause, few
follicles remain, yet intermittent estradiol production from the ovaries
may still occur. (8,9) Adrenal androstenedione is the primary source of
estrogen after menopause; sex hormone-binding globulin falls slightly.
(10) FSH levels remain high for several years after menopause,
after which levels decline considerably. (10,11)
Although FSH is commonly used, there are no consistently reliable
endocrine markers to establish a woman’s menopausal status. (9) Shifts
in hormones contribute significantly to a sense of physical,mental, and
emotional imbalance that may characterize a woman’s experience of
menopause. As a clinician, it is important to note the changes that
occur,link them to the physiology of the various hormones,and address
imbalances individually. Addressing other aspects of endocrine health is
also necessary and may involve assessing adrenal and liver function,
as well as diet, exercise, and other lifestyle factors.
Problems with Conventional HRT
In July 2002, after determining that estrogen in combination with
progestin increased a woman’s risk of breast cancer, coronary events,
stroke, and blood clots, the National Institutes of Health
(NIH)prematurely halted the first part of the WHI, a study designed to
identify the risks and benefits associated with long-term hormone use.
In this study, 16,608healthy postmenopausal women with a uterus,
ages50-79, were randomized to either test or placebo group. (4) The
test group received a combination of equine estrogen and synthetic
progestin (PremPro®);no bioidentical hormones were used. At the time
the study was halted, PremPro compared to placebo resulted in:
- t26-percent increased risk of invasive breast cancer (eight additional cases per 10,000 women per year);
- t29-percent increased risk of myocardial infarction (MI) or death
from coronary heart disease (CHD) (seven additional cases per 10,000
women per year);
- t41-percent increased risk of stroke (eight additional cases per 10,000 women per year);and
- t200-percent increased risk of blood clots (18 additional cases per 10,000 women per year).
- The WHI study also confirmed benefits seen in previous studies, most notably:
- t33-percent decreased risk of hip fracture (five fewer fractures per 10,000 women per year);
- t37-percent decreased risk of colorectal cancer (six fewer cases per 10,000 women per year); and
- tRelief of menopausal symptoms like hot flashes and vaginal atrophy.
An ancillary study the following year, the Women’s Health Initiative
Memory Study (WHIMS),demonstrated additional risks for women on
combination equine estrogens and synthetic progestins. The study found
combination therapy doubled the risk of developing dementia in women age
65 and older. (12)
Even prior to the WHI and WHIMS studies,relatively few women who
might benefit from HRT chose to use it, despite the previous findings
that HRT has established benefits for the treatment of menopausal
complaints, reduction in bone loss, and some beneficial effects on the
cardiovascular system. (13-15) In addition, women prescribed HRT often
discontinue it before long-term benefits are realized. The most common
reasons for discontinuation of HRT are unwanted side effects and weight
gain, with one-third to two-thirds of women discontinuing it within the
first two years. (13,14,16-18) Most side effects are attributed to the
synthetic progestin portion of HRT, with the most common complaints
being bloating, breast tenderness, and irregular bleeding. (13,14,19)
Secondary reasons for discontinuation include fear of cancer and
recommendation by a physician.
For women not initiating HRT, reasons cited include: HRT perceived as
unnecessary, a preference to not take medications, a fear of the
effects of long-term HRT, confusion over the scientific information as
presented in the media, and the view that menopause is a natural event.
(2,3,14,20) Use of HRT was correlated with older women’s wishes to
reduce osteoporosis risk, while younger women sought relief from
menopausal symptoms, predominantly vasomotor flushing. (2,19) Given this
information, it should follow that utilizing hormones that have fewer
side effects andrisks, correlate with a woman’s perception of
"natural,” and address long-term health benefits could increase hormone
use and therefore improve a woman’shealth and well-being. Bioidentical
hormones mayprovide these benefits.
What is Bioidentical HormoneTherapy?
Bioidentical hormones are identical to hormones produced
endogenously. In the case of HRT,these include estrone (E1), estradiol
(E2), estriol(E3), and progesterone (P4). Although
bioidenticalhormones have long been utilized in other countries,the
United States has predominantly used non-bioidentical hormones for the
past 40-45 years, beginning with the introduction of oral contraceptives
inthe early 1960s.
The differences in the actions, risks, and benefits of various
hormones depend on numerous factors, including method of administration,
absorption,bioavailability, metabolism, receptor affinity, receptor
specificity, and molecular structure. (21,22)
Bioidentical versus SyntheticEstrogens
The body naturally produces three mainforms of estrogen: estrone,
estradiol, and estriol. Bioidentical estrogens are molecularly identical
to these naturally produced estrogens. Synthesized in the ovaries and
metabolized in the liver, estradiol is the mostphysiologically active
form of estrogen. Increased serum estradiol levels are linked to an
increased risk ofbreast and endometrial cancer. (23) Estrone is
converted reversibly from estradiol in the liver and small intestine and
increases after menopause when the adrenalglands play a more prominent
role than the ovaries inhormone synthesis. Like estradiol, increased
estronelevels are linked to an increased risk of estrogen-receptor
positive (ER+) breast cancer and an increase in breast density, an
independent risk factor for breast
Table 1. Synthetic and Bioidentical Estrogen Preparations Available in the United States
Table 2. Synthetic Progestin and Bioidentical Progesterone Preparations Available in the United States
(24,25) Both estradiol and estrone can be metabolized to estriol, which
is the primary urinary metabolite. Estriol is considered the "weakest”
estrogen, as it has a shorter-acting effect than estradiol or estrone.
(26) However, depending on sufficient dosing and route of application,
estriol can attain a full estrogenic effecton target tissue, such as
the vaginal mucosa. (26) Estriolremains intact when supplemented orally
(i.e., unlike estradiol, estriol is not converted to estrone, nor is
it converted to estradiol). (27) In Europe and China, estriolis
commonly used for HRT. A comprehensive review of the safety and efficacy
of estriol suggests it maybe safer than estrone or estradiol, but can
still have a stimulatory action on the endometrium and breastwhen given
in high doses. (28)
In a comparison of bioidentical (estropipate,estradiol) versus
non-bioidentical estrogens (ethinylestradiol, conjugated equine
estrogens, diethylstilbestrol), non-bioidentical estrogens had
significantly exaggerated responses across multiple hepatic
and non-hepatic measures of estrogenic effects. (29)
The predominant estrogen currently prescribed in the United States is
Premarin, a brand name for conjugated equine estrogens (CEE).
Premarincontains approximately 100 distinctly different estrogens,
mainly estrone sulfate, equilins, equilenins, and alpha-estradiol, all
of which are estrogens occurring naturally in horses; with few natural
to the human body. Over 30-percent drop in sales revenues from both
Premarin and PremPro occurred following reports of the WHI study. (30)
Many estrogen formulations presently available in the United States
contain bioidentical estrogens (Table 1). A growing number of
conventional and CAM physicians are now prescribing "Tri-Est,”or
"Bi-Est,” nicknames given to individually-compounded formulations of
estriol, estrone and estradiol, or estriol and estradiol, respectively.
Licensed pharmacists can fill a doctor’s prescription for
these combinations of natural estrogens in a variety of doses and
delivery systems to specifically address patient needs.
Natural Progesterone versus Synthetic Progestins
Inconsistency in use of the terms "progesterone,” "progestin,” and
"progestogen” has led to confusion over these substances. Progesterone
refers to a single (note the "one” at the end of the term)molecular
structure that is identical to the progesterone molecule that the body
makes, also referred to biochemically as "P4.” Progestogen is the
category of hormone molecules (natural and synthetic) that act like
progesterone in the uterus. Progestin generally refers to synthetic
progestogens. See Table 2 for a list of commonly prescribed
Progesterone was originally procured by extraction methods from
animal placenta. Natural progesterone products today are produced in a
laboratory setting via a process designated as the "Marker Degradation”
from saponins found in soy and Dioscoreavillosa (wild yam). Hudson
presents a detailed historic perspective of the series of events
surrounding the discovery of this process. (31)
Progesterone was first used as HRT in 1934for the treatment of
ovariectomized women. (32) Due to significant first-pass effect of
progesterone, synthetic progestins were developed in the 1940s, either
fromprogesterone (e.g., medroxyprogesterone acetate) or from
testosterone (e.g., 19-nortestosterone). (33) Progestins mimic the
body’s progesterone closely enough to bind to progesterone receptor
sites, but do not deliver the full range of "messages” a natural
progesterone molecule does. A synthetic progestin, for example,may have
similar effects on the endometrium, yet can initiate widely different
actions elsewhere in the body (e.g., brain, mineralocorticoid receptors,
etc.)depending on the classification of the particular progestin
(nortestosterone derivatives, ethyl-13 derivatives, progesterone
derivatives, or norprogesterone derivatives.) (34,35) These different
progestins have been mapped as to affinity to androgen,
progesterone,glucocorticoid, and estrogen receptors. (36) In
contrast to progesterone, 19-nortestosterone derivatives are known to
have estrogenic properties, which could be attributed to their estrane
structure (an 18-carbon tetracyclic hydrocarbon nucleus that is the
parent structure to all estrogens) or to the production of estrogenas a
metabolite. (37) Derivatives of 19-nortestosteronehave been shown to
increase the growth of ER+breast cancer cells in vitro. (38) A paper
published in 2000 discussed the development of newer synthetic
progestins that more closely fit the profile of
bioidentical progesterone. (39)
Estrogen, Progesterone, or Both?
Current recommendations from the American College of Obstetricians
and Gynecologists suggest that estrogens be prescribed in conjunction
with progestins (to prevent endometrial hyperplasia) when a woman has an
intact uterus; (40) conversely, unopposed estrogens are the norm
post-hysterectomy. Although progesterone and estrogen receptors both
exist in tissue outside the uterus, it has not been thought necessary to
provide progestins after the uterus is removed.
In contrast, when using natural hormones,many physicians consider
the concomitant use of progesterone with estrogen to be an important
aspect of bioidentical hormone therapy and hormonal balancing. The
growing research on the synergism of thesetwo hormones, as well as an
expanded understanding of progesterone’s effect in the body, are
prompting some to recommend these hormones be prescribed together,
regardless of the presence or absence of auterus. (41,42)
When considering estrogen replacement during perimenopause and early
menopause, thelevel of endogenous estrogen production must also be
considered, since elevated FSH levels can be associated with either
increased or decreased levels of estrogen. (9,11) Since progesterone
levels can fall first with the advent of an ovulatory cycles, some
women may do well with progesterone-only supplementation during
perimenopause, which may help balance the effects of unopposed
endogenous estrogen production. FSH, although commonly used as a
diagnostic indicator of menopause, may not be the most reliable tool for
determining estrogen needs perimenopausally. (9) One should also note
that women with a greater amount of body fat can produce a significant
amount of endogenous estrogen postmenopausally. This can occur
exclusively through aromatization of estrogen sfrom adrenal
and rostenedione by the fat cells. (10) In one study, 10-15 percent of
postmenopausal women produced enough estrogen to build the
endometrial lining, further emphasizing the need to
determine individually the potential hormonal needs of each woman during
Hormone function can be affected by the presence of other hormones,
as is seen in the synergistic effects of E2 and P4. (41,43) Even the
receptors can exhibit synergism, although the exact mechanisms have not
been fully elucidated. (44,45) An example of this phenomenon in clinical
practice is the synergistic antiovulatory effects of estrogen and
progestogens resulting in efficacy of lower-dose oral
contraceptives equal to that of higher-dose regimens. More recently,a
study found estradiol in combination with progesterone inhibited bone
resorption to a greater degree than either hormone alone. (46)
Differences in Hormone Delivery
Continuous versus Pulsed Delivery
There is sufficient evidence to suggest the pulsatile delivery of
estrogen and progesterone that occurs naturally serves to enhance the
functioning of these hormones in the body. (47-49) In theory,
continuous application of hormones may serve to down-regulate receptors,
contributing to a general decrease in the activity of those particular
hormones. Research has demonstrated that sequential pulsed estrogen
and progestin therapy allows for smaller amounts of hormones to be used.
(47) Reduced dosage would translate to reduced likelihood of unwanted
side effects as well as a reduced impact on the liver via metabolism
of supplemented hormones. This also supports the most recent U.S. Food
and Drug Administration recommendation surrounding hormone therapy for
women that advocates using the lowest effective dose for the least
amount of time necessary. (50)
Routes of Administration
Many different routes of delivery are available for natural hormones,
including oral, transdermal (patch), percutaneous (cream, gel),
intramuscular(IM), subcutaneous, sublingual, vaginal (gels,
cream,tablet, ring, and pessary), and nasal. The route
of administration can confer differences in absorption,metabolic
pathway, and bioavailability. In general,the oral route leads to more
rapid metabolism and a greater impact on hepatic processes, requiring
larger doses than those bypassing the entero-hepatic circulation. The
same sized doses of progesterone and estradiol resulted in greater
circulating blood levels when delivered vaginally compared to oral
administration, due to entero-hepatic metabolism. (51) In comparing
different E2 delivery systems, percutaneous, transdermal, and vaginal
delivery resulted in a reduction in metabolism to E1 via the
entero-hepatic circulation. (51-53) Side effects common with oral E2
were not seen when administration was via the percutaneous or
transdermal routes. (54,55)
Approximately 90 percent of oral progesterone is metabolized by the
"first pass effect” (caused by shunting through the entero-hepatic
circulation),leading to difficulties in dosing as well as an
abrupt increase in 5-alpha-progesterone metabolites. (56)
Oralprogesterone administration resulted in higher levels of
progesterone metabolites (deoxycorticosterone, deoxycorticosterone
sulfate, and 5-alpha and betapregnenolone) when compared to vaginal
administration. (51-57) A study by Hermann et al compared 80
mg progesterone daily via a topical cream (Pro-Gest®)to 200 mg oral
micronized progesterone (OMP) as Prometrium®daily and found no
difference between the two products with respect to steady-state
blood levels of progesterone as measured by area under thecurve (AUC).
(58) In another comparison study, similar endpoints were achieved with
300 mg oral micronized progesterone and 90 mg vaginal progesterone,with
fewer side effects of drowsiness noted with the vaginal application (an
effect attributed to 5-alphaand beta metabolites of progesterone).
It is important to note that progesterone and its metabolites have
differing effects in the brain,uterus, smooth muscle, and oocyte. (60)
For example,depressive effects of progesterone are
predominantly attributed to pregnane metabolites, such as
allopregnanolone, as opposed to progesterone itself. Given the increase
in metabolites seen with OMP, vaginalor topical delivery systems may
reduce expression of side effects attributed to these metabolites.
Because numerous factors can influence intestinal absorption and
metabolism, some preparations may have more variable effects. In a study
of the pharmacokinetics of oral versus IM administration ofE2, 4 mg IM
demonstrated a rate of release into the bloodstream that achieved
therapeutic levels over 2-4weeks (depot effect). To achieve the same
therapeutic equivalency with an oral dose, some individuals required as
much as 2 mg daily for three weeks. (61)
Oral micronized progesterone also exhibits substantial variability in
absorption among individuals. In one study, maximum serum
concentration ranged from 15.72-625.98 ng/mL, following a single300 mg
dose; the authors also noted that absorption increased with age. (62) In
a separate study of percutaneous absorption of a progesterone cream,
the authors reported moderate variability among individuals. (63)
Forms of Administration
The base of a cream, gel, or suppository can also affect absorption.
In a study of topical applications comparing progesterone in a
hydrophilic gel, lipophilic base, and emulsion-type base, (64) the
emulsion-type base led to a two-fold greater AUC and peak plasma
concentration than either the hydrophilicgel or lipophilic base. (64)
Another study by the same authors comparing two suppository bases found
anemulsion-type base resulted in improved pharmaceutical availability
when compared to a lipophilic baseof cocoa butter. (65) A comparison
between the percutaneous and vaginal delivery systems found the
elimination half-life for the three transdermal forms ofprogesterone
was in the range of 30-40 hours, (64) compared to the cocoa butter
vaginal suppository with anelimination half-life of 9-10 hours and the
emulsionbased suppository with an average elimination halflife of 14
Physiological levels of serum progesteronewere reached via a novel
nasal spray application. (66) Also unique is an effervescent
progesterone vaginaltablet that results in adequate serum progesterone
levels. In this study there was significant age-related difference in
time of maximum concentration (Tmax),with women over 40 years attaining
a lower Tmaxthan younger women. (67)
Given the differences that abound in both thetype and route for
administration of hormones, physicians should assess an individual
woman’s need forhormone therapy and tailor the regimen to her needs.
Effect of Hormones on theCardiovascular and EndocrineSystems
Hormones have multiple effects on the cardiovascular and endocrine
systems, including eliciting actions on blood pressure, vascular tone,
hemostasis, lipid metabolism, cardiac vasospasm, andglucose metabolism.
Blood Pressure Effects
Progesterone antagonizes mineralocorticoidssuch as aldosterone.
Since aldosterone enhances sodium retention and potassium loss via the
urine, antagonism of this effect results in increased sodiumexcretion
in the urine. This effect on sodium loss hasbeen shown to reduce blood
pressure in hypertensivepatients in some studies, as well as ease
symptoms ofwater retention. (68,69) This anti-mineralocorticoid
effectis not seen with the majority of available syntheticprogestins.
Moreover, some progestins enhance estrogen activity, contributing to the
potential for increased blood pressure. (70,71)
In normotensive patients, progesterone candecrease sympathetic
vascular tone, without concomitant drop in blood pressure. (72)
Progesterone acts viathe nitric oxide pathway to enhance vasodilation
andimprove microcirculation. (73,74) In animal studies, endogenous and
low-dose parenteral E2 have also beenshown to increase vasodilation.
Estrogen replacement therapy is known toincrease the risk of blood
clots. High-dose estrogens,especially synthetic and oral estrogens,
increase liverprotein synthesis, including coagulation factors.
Oralestrogens also increase angiotensin, and may raiseblood pressure
and stroke risk in susceptible women. (70) In a randomized crossover
study, estriol did notaffect hemostatic function, whereas ethinyl
estradioldecreased prothrombin time while increasing plasminogen and
factor VII. (75) In the WHI study, CEEwith medroxyprogesterone acetate
(MPA) was shownto increase blood-clotting events. (76)
In contrast to synthetic hormone use, a recentstudy evaluating
progesterone cream for safety andefficacy found no markers for
inflammation or clotting. (77) The study also found that in women with
higher than normal cortisol levels, there was a marked decline in the
level of cortisol to the normal range whileusing progesterone cream
compared to placebo. (77)
Hormone Effects on Lipids,Atherosclerosis, Vasospasm, and InsulinResistance
Activated by stress, increased cortisol hasbeen associated with an
increased risk of atherosclerosis, obesity, and other manifestations of
heart disease. Cortisol can contribute to atherosclerosis by increasing
cholesterol ester formation. While estrogenwas seen to have no effect
on cholesterol esters, progesterone blocked cholesterol ester formation,
signifying an anti-atherogenic effect of progesterone. (78)
Whereas some synthetic progestins areknown to exert a negative
effect on blood lipids, bioidentical progesterone does not appear to do
so. (79,80) Inthe Postmenopausal Estrogen and Progestin Interventions
(PEPI) Trial, oral micronized progesterone faredsignificantly better
than MPA, as OMP did not bluntthe beneficial effects of estrogen on HDL
elevation. (81) This was also found in an earlier study
comparingprogesterone with both nortestosterone and MPA. (82)
Third generation progestins, such as norgestimate and desogestrel,
have not demonstrated thissame adverse effect on serum lipids. (83)
MPA increases the extent of atherosclerosisin coronary arteries,
suppresses the protective effect of estrogen on arterial injury,
increases insulinresistance, and attenuates the beneficial effects
ofestrogen on vasodilation. (84-86) This is consistent withfindings
that synthetic estrogen as well as 19-nortestosterone can result in a
decrease in glucose tolerance, whereas glucose metabolism is unaffected
byP4. (87) Progesterone has furthermore been shown tohave an
antiproliferative effect on vascular smoothmuscle in normal human and
animal tissues as wellas in models simulating hyperinsulinemia and
In two studies comparing E2 and P4 with E2and MPA, E2 and P4
protected against coronary hyper-reactivity and subsequent coronary
vasospasm,whereas coronary vasospasm was increased in monkeys receiving
MPA. (90,91) In a separate study, the sameauthors demonstrated an
inhibition of coronary vasospasm with topical progesterone cream in
pre-atherosclerotic primates. (92)
One study comparing MPA to progesteronedemonstrated progesterone
reduced the risk for arteriosclerosis by inhibiting vascular cell
adhesionmolecule-1 (VCAM-1), whereas MPA did not. (93) Thediffering
effects of progesterone and MPA supportprogesterone as a better option.
Progesterone and 17beta-estradiol both inhibited cardiac fibroblast
growth, with the effectsof 17beta-estradiol enhanced by P4, suggesting
thecombination may help protect postmenopausal women against
cardiovascular disease. (94)
Normal liver function is essential for lipidmetabolism. Synthetic
progestins retain undesirableeffects on liver metabolism, even when
administeredthrough the skin. (83) In regard to estrogen, a comparison
between orally administered ethinyl estradiol(EE) and E2 demonstrated
beneficial effects on serumlipids (EE>E2); however, EE demonstrated a
markedincrease in liver protein synthesis, including sex-hormone
binding globulin (SHBG) and pregnancy zoneprotein (PZP), markers of
increased estrogenic effect. (95) SHBG elevation can result in lower
testosterone activity due to its greater affinity to testosteroneand
dihydrotestosterone than estrogen.
Natural progesterone, in either oral, vaginal,or topical
administrations, has demonstrated safety inits effects on lipid
metabolism and blood clotting. (77,80,96) The research to date looking
at cardiovascular riskpoints to bioidentical hormones, particularly
progesterone, as the hormone therapy of choice to supporthealthy
The Effect of Hormones on the Breast
In the past, the effect of synthetic progestinson the breast was
unclear. Whereas progestins havebeen used historically to treat some
forms of advancedbreast cancer, a re-evaluation of results of a
cohortstudy suggest an increased risk in the occurrence ofbreast
cancer in women using combined HRT (predominantly CEE plus MPA) beyond
that seen withunopposed estrogen; the risk increase, however, wasnot
statistically significant. (97) Recently, the effect ofHRT on breast
tissue was demonstrated in the WHIstudy. A 26-percent increased risk of
invasive breastcancer was seen in women using a combination ofCEE and
MPA compared to placebo. (4)
Several reviews suggest a protective effectof progesterone and some
progestins on normal andpathological breast tissue, including a strong
anti-proliferative effect both in the presence and absence ofestrogens.
(98-102) Low endogenous progesterone levelswere also correlated with a
five-fold increase in premenopausal breast cancer risk in women
experiencing infertility when compared with infertile womenwith normal
hormone levels. (103) In women undergoing breast surgery for benign
breast conditions, pretreatment with topical estrogen resulted in
increasedepithelial proliferation compared to a reduction
inproliferation seen with percutaneous progesteronetreatment;
furthermore, progesterone reduced estrogen-induced proliferation when
both treatments wereused. (104) An in vitro study evaluating the
effect ofprogesterone on the growth of T47-D breast cancercells
demonstrated increased apoptosis as mediatedby the regulation of genes
controlling apoptosis. (105) Ina review by Desreux et al, the authors
emphasizedprogesterone’s role in supporting healthy breast homeostasis.
(106) Progesterone opposes the proliferativeeffects of estradiol in
the breast, (106,107) a role not seenwith synthetic progestins. (106)
A large cohort study involving 1,150 Frenchwomen with benign breast
disease showed no increase in breast cancer risk with women using
topical progesterone cream (RR=0.8), a common European treatment for
breast mastalgia. Furthermore,the researchers noted a decrease in
breast cancer riskamong women using progesterone cream plus an
oralprogestogen (RR=0.5), compared with women usingoral progestogens
Two recent studies point to a difference inbreast cancer risk when
comparing synthetic progestins to bioidentical progesterone as a part of
theHRT regimen. A French cohort study involving 3,175postmenopausal
women predominantly using naturalHRT (83 percent using transdermal
estradiol and anon-MPA progestogen – progesterone and others)found no
increased risk in users of these forms ofHRT.109The French E3N-EPIC
cohort study is probably the most significant examination of the
differences between progestogens and breast cancer risk.It assessed the
risk of breast cancer associated withHRT use in 54,548 postmenopausal
women and foundthe risk was significantly greater (p<0.001) with
HRTcontaining synthetic progestins (RR=1.4 [1.2-1.7])than with HRT
containing micronized progesterone(RR=0.9 [0.7-1.2]). (110) Although
there are no prospective trials looking at the safety of
bioidenticalprogesterone with respect to the breast, these largecohort
studies, in combination with studies examining the effects of
progesterone on normal and cancerous breast cells, do provide enticing
evidence for thesafety of bioidentical progesterone.
It is well understood that, due to proliferativeeffect on normal
breast cells as well as on numerousbreast cancer cell lines, estrogens
are contraindicatedfor women at risk for breast cancer, because, as
referenced above, increased estrone and estradiol levelsare associated
with an increased risk of breast cancer.The supplementation of either
of these forms of estrogen increases serum estradiol and estrone due
tothe pathways by which they are metabolized. In contrast, several
studies have demonstrated an inverserelationship between estriol levels
and breast canceras well as antitumor effects of estriol. (27,
111-113) However, while there is reason to believe that estriol inlow
doses could be protective for the breast in someindividuals, when
supplementing estrogens, one mustalso consider the differences among
individuals withrespect to metabolism. A recent study looking at
theeffects of 14 different endogenous estrogen metabolites demonstrated
proliferative, antiproliferative, andbi-phasic effects on a specific
human breast cancerline (MCF-7), further emphasizing the importance
ofindividualized consideration. (114)
The Effect of Hormones on theEndometrium
Both OMP and vaginal delivery of progesterone result in sufficient
end-organ effect on the uteruswith doses beginning at 100 mg daily x 25
days/month or 45 mg every other day for six doses/month,respectively.
(83,115,116) Similar end-organ results havebeen seen using percutaneous
progesterone cream. (117)
Hormones and Menopausal Symptoms
Although most physicians attribute vasomotor flushing to a lack of
estrogen, progestogens canhave a beneficial effect. (118) A study using
a progesterone cream applied to the skin resulted in a
significantreduction in the number and intensity of hot flashes in83
percent of the study participants, as well as benefits in other
quality-of-life measurements.(119) In a separate study, subjects
receiving 20 mg of topical progesterone cream daily for four weeks
demonstratedsignificant improvement of menopausal symptoms,measured by
Greene Climacteric Scale scores. (77)
In a study comparing the effects of CEE plusMPA to CEE plus OMP in
postmenopausal women,the latter group had significantly improved sleep
efficiency over the synthetic progestin group. (120) Anotherstudy
comparing MPA to OMP found micronizedprogesterone to be better
tolerated than MPA, as wellas conferring additional benefits in
cognition and improvement of menstrual problems. (121)
Oral and transdermal estradiol preparations have been found to confer
benefit for menopausal symptoms and vaginal cytology, as well asreduce
bone loss in postmenopausal women. (53,55) Estriol has also been
demonstrated to reverse vaginalatrophy. (122,123) Estriol doses must be
increased up tothree times the dose of estradiol to achieve
similareffects (e.g., reducing hot flashes and vaginal drynessin
menopausal women) and is typically dosed twicedaily to achieve steady
blood levels. (27)
Hormones and Bone Health
Bone turnover increases at menopause andmay remain high for 25 or
more years following thelast menstrual cycle. (124) Hormonal control of
boneturnover is not limited to a single hormone, but ratherthe
complex interrelationship of a number of steroidand other hormones,
including estrogen, progesterone, testosterone, corticosteroids, vitamin
D, thyroidhormones, and retinoids. (125) When given alone, estrogens
have a known beneficial effect on limiting boneloss as well as reducing
the number of fractures. Studies with progesterone alone are mixed.
Progesteronesupports bone health through its effects on the
proliferation and differentiation of human osteoblasts. (126) Several
animal and human studies have demonstratedprogesterone’s positive
effect on bone formation aswell as inhibition of bone
resorption.(127-130) However,double-blind placebo-controlled studies in
humanshave yet to demonstrate a significant increase in bonemineral
density (BMD) or a reduction in fracturerate with progesterone alone.
One short-term humanstudy of OMP showed no difference in markers
ofbone resorption compared to placebo.(131) Longer-termstudies
evaluating BMD and fracture rate are neededto determine the value of
progesterone supplementation alone for preventing or treating
osteoporosis.Several studies looking at estrogen and
progesteronesupplementation suggest estrogen and progesteronehave
distinct and complementary roles in the maintenance of bone.(46,130,132)
Testosterone can also decreaseurinary calcium loss and bone
Hormones and the Brain
Progesterone has numerous beneficial effectson the brain and nervous
system, including supporting myelin formation and activating GABA
receptors.(134) Progesterone also plays a role in the reductionof
ischemia in the brain and decreasing the inflammatory response after
traumatic brain injury.(135,136) Areview of progesterone’s effect on
the brain suggestsviable therapeutic possibilities for the prevention
andtreatment of neurodegenerative diseases, as well asfor repair
processes and preservation of cognitivefunction with age. (137)
Synthetic progestins do not sharethese physiological effects. In fact,
the WHIMS foundequine estrogen plus synthetic progestins
(PremPro)doubled the risk of developing dementia in womenage 65 and
Estrogens have known physiological effectson the brain, including
improved blood flow via vasodilation and stimulation of serotonin and
norepinephrine, which can impact nerve cell function and mood.It was
postulated that estrogen could help delay age-related cognitive decline
or help prevent Alzheimer’s disease, and small studies on animals
appearedto confirm this.138However, two large-scale humanstudies
failed to demonstrate any significant benefitof estrogen
supplementation on cognitive function.
The Atherosclerosis Risk in Communities(ARIC) study evaluated the
effects of estrogen onmemory and cognitive function in 2,000 women
participants ages 48-67 over a 10-year period and foundno correlation
(either positive or negative) betweenestrogen and cognitive
The WHIMS also failed to demonstrate acognitive benefit for estrogen
alone. In fact, resultsdemonstrated an increased risk for dementia in
women using estrogen alone, although not as great a riskas combined
synthetic HRT.12It should be noted thatthe WHIMS utilized equine
estrogens with or without MPA, while the prospective ARIC study did not
denote estrogens utilized.
The use of bioidentical hormone therapy iswell tolerated, provides
symptom relief, and can address many of the health needs as well as the
individual preferences of menopausal and perimenopausalwomen.
Physicians are encouraged to take the timeand effort to help women
determine the regimen thatbest suits their needs, including testing
hormone levels directly prior to supplementation and using theleast
amount necessary to achieve the desired results.This effort will
undoubtedly pay off in fewer unwanted side effects and greater quality
1. Wetzel W. Human identical hormones: real people,real problems, real solutions. Nurse Pract Forum1998;9:227-334.
2. Andrist LC. The impact of media
attention, familyhistory, politics and maturation on women’sdecisions
regarding hormone replacement therapy.Health Care Women Int
3. Hunter MS, O’Dea I, Britten N.
Decision-makingand hormone replacement therapy: a qualitativeanalysis.
Soc Sci Med 1997;45:1541-1548.
4. Rossouw JE, Anderson GL, Prentice
RL, et al.Risks and benefits of estrogen plus progestin inhealthy
postmenopausal women: principal resultsFrom the Women’s Health
Initiative randomizedcontrolled trial. JAMA 2002;288:321-333.
5. Johannes CB, Crawford SL. Menstrual
bleeding,hormones, and the menopausal transition. SeminReprod
6. Richardson SJ. The biological basis of themenopause. Baillieres Clin Endocrinol Metab1993;7:1-16.
7. Burger HG. The endocrinology of the menopause. JSteroid Biochem Mol Biol 1999;69:31-35.
8. Klein NA, Soules MR. Endocrine changes of theperimenopause. Clin Obstet Gynecol 1998;41:912-920.
9. Burger HG. Diagnostic role of
folliclestimulating hormone (FSH) measurementsduring the menopausal
transition – an analysisof FSH, oestradiol and inhibin. Eur J
10. Burger HG. The endocrinology of the menopause.Maturitas 1996;23:129-136.
11. Speroff L, Glass RH, Kase NG.
ClinicalGynecologic Endocrinology and Infertility. 6th
ed.Philadelphia, PA: Lippincott, Williams & Wilkins;1999.
12. Shumaker SA, Legault C, Rapp SR, et
al. Estrogenplus progestin and the incidence of dementia andmild
cognitive impairment in postmenopausalwomen: the Women’s Health
Initiative MemoryStudy: a randomized controlled trial.
13. Vihtamaki T, Savilahti R, Tuimala
R. Why dopostmenopausal women discontinue hormonereplacement therapy?
14. Newton KM, LaCroix AZ, Leveille SG,
et al.Women’s beliefs and decisions about hormonereplacement therapy.
J Womens Health 1997;6:459-465.
15. Legare F, Godin G, Guilbert E, et
al. Determinantsof the intention to adopt hormone replacementtherapy
among premenopausal women. Maturitas2000;34:211-218.
16. den Tonkelaar I, Oddens BJ.
Determinants of longterm hormone replacement therapy and reasons
forearly discontinuation. Obstet Gynecol 2000;95:507-512.
17. Ettinger B, Pressman A.
Continuation ofpostmenopausal hormone replacement therapy in alarge
health maintenance organization: transdermalmatrix patch versus oral
estrogen therapy. Am JManag Care 1999;5:779-785.
18. Bjorn N, Backstrom T. Compliance to
HRT: thesignificance of negative side effects and moodsymptoms.
Abstract: Eighth Annual Meeting ofNAMS. Menopause 1997;4:283.
19. Ettinger B, Pressman A, Silver P.
Effect of ageon reasons for initiation and discontinuationof hormone
replacement therapy. Menopause1999;6:282-289.
20. Perrone G, Capri O, Borrello M,
Galoppi P.Attitudes toward estrogen replacement therapy.Study
conducted on a sample population ofwomen attending an ambulatory care
center forthe treatment of menopause. Minerva Ginecol1993;45:603-608.
[Article in Italian]
21. Leake R. Contents of HRT and mechanismsof action. J Epidemiol Biostat 1999;4:129-133;discussion 133-139.
22. Huber JC, Campagnoli C, Druckmann
R, et al.Recommendations for estrogen and progestinreplacement in the
climacteric and postmenopause.European Progestin Club. Maturitas
23. Kabuto M, Akiba S, Stevens RG, et
al. Aprospective study of estradiol and breast cancer inJapanese
women. Cancer Epidemiol BiomarkersPrev 2000;9:575-579.
24. Miyoshi Y, Tanji Y, Taguchi T, et
al. Association ofserum estrone levels with estrogen
receptor-positivebreast cancer risk in postmenopausal Japanesewomen.
Clin Cancer Res 2003;9:2229-2233.
25. Ursin G, Palla SL, Reboussin BA, et
al. Posttreatment change in serum estrone predictsmammographic percent
density changes inwomen who received combination estrogenand
progestin in the postmenopausal estrogen/progestin interventions (PEPI)
trial. J Clin Oncol2004;22:2842-2848.
26. van der Vies J. The pharmacology of oestriol.Maturitas 1982;4:291-299.
27. Follingstad AH. Estriol, the forgotten estrogen?JAMA 1978;239:29-30.
28. Head KA. Estriol: safety and efficacy. Altern MedRev 1998;3:101-113.
29. Mashchak CA, Lobo RA, Dozono-Takano
R, etal. Comparison of pharmacodynamic propertiesof various estrogen
formulations. Am J ObstetGynecol 1982;144:511-518.
30. http://www.pharmafocus.com/cda/focusH/1,2109,21-0-0-JUN_2004-focus_news_detail-0-225648,00.html [Accessed July 26, 2006]
31. Hudson T. Wild yam, natural
progesterone:unraveling the mystery. The Townsend Letter forDoctors
and Patients 1996;July:156.
32. Hirvonen E. Progestins. Maturitas 1996;23:S13-S18.
33. Gompel A. Progestin treatments of menopause. RevPrat 1993;43:2645-2650. [Article in French]
34. Belaisch J. Chemical classification of syntheticprogestogens. Rev Fr Gynecol Obstet 1985;80:473-477. [Article in French]
35. Fuhrmann U, Krattenmacher R, Slater
EP,Fritzemeier KH. The novel progestin drospirenoneand its natural
counterpart progesterone:biochemical profile and antiandrogenic
36. Ojasoo T. Multivariate preclinical evaluation ofprogestins. Menopause J North Am Menopause Soc1995;2:97-107.
37. Kamada M, Irahara M, Aono T. Action of syntheticprogestin. Nippon Rinsho 1994;52:593-599.[Article in Japanese]
38. Jordan VC, Jeng MH, Catherino WH,
Parker CJ.The estrogenic activity of synthetic progestins usedin oral
contraceptives. Cancer 1993;71:1501-1505.
39. Negro-Vilar A. New progestins and potentialactions. J Soc Gynecol Investig 2000;7:S53-S54.
40. http://www.acog.org/from_home/publications/press_releases/nr10-01-04.cfm [Accessed July 26,2006]
41. Chambon Y. Synergism and antagonism
betweenestrogens and progestins: an update. Bull Acad NatlMed
1993;177:177-186. [Article in French]
42. Hargrove JT, Osteen KG. An
alternative methodof hormone replacement therapy using the naturalsex
steroids. Infertility Reprod Med Clin North Am1995;6:653-674.
43. Saffran J, Loeser BK, Faber LE.
Effects ofprogestins on the progesterone receptor in guineapig uterus.
Adv Exp Med Biol 1979;117:223-239.
44. Cato AC, Ponta H. Different regions
of the estrogenreceptor are required for synergistic action withthe
glucocorticoid and progesterone receptors. MolCell Biol
45. Bradshaw MS, Tsai SY, Leng XH, et
al. Studies onthe mechanism of functional cooperativity
betweenprogesterone and estrogen receptors. J Biol
46. Schmidt IU, Wakley GK, Turner RT.
Effectsof estrogen and progesterone on tibiahistomorphometry in
growing rats. Calcif Tissue Int2000;67:47-52.
47. Casper RF. Estrogen with interrupted progestinHRT: a review of experimental and clinical studies.Maturitas 2000;34:97-108.
48. Casper RF, MacLusky NJ, Vanin C,
Brown TJ.Rationale for estrogen with interrupted progestin asa new
low-dose hormonal replacement therapy. JSoc Gynecol Investig
49. DeSombre ER, Kuivanen PC. Progestin
modulationof estrogen-dependent marker protein synthesis inthe
endometrium. Semin Oncol 1985;12:6-11.
50. http://www.fda.gov/bbs/topics/NEWS/2003/NEW00938.html [Accessed July 26, 2006]
51. Nahoul K, Dehennin L, Jondet M,
Roger M.Profiles of plasma estrogens, progesterone and
theirmetabolites after oral or vaginal administration ofestradiol or
progesterone. Maturitas 1993;16:185-202.
52. Lyrenas S, Carlstrom K, Backstrom
T, von SchoultzB. A comparison of serum oestrogen levels
afterpercutaneous and oral administration of oestradiol-17 beta. Br J
Obstet Gynaecol 1981;88:181-187.
53. Selby P, McGarrigle HH, Peacock M.
Comparisonof the effects of oral and transdermal
oestradioladministration on oestrogen metabolism, proteinsynthesis,
gonadotrophin release, bone turnover andclimacteric symptoms in
postmenopausal women.Clin Endocrinol (Oxf) 1989;30:241-249.
54. Palacios S, Menendez C, Jurado AR,
Vargas JC.Effects of oestradiol administration via differentroutes on
the lipid profile in women with bilateraloophorectomy. Maturitas
55. Pattison NS, Uptin T, Knox B,
France J.Transdermal oestrogen for postmenopausal women:a double blind
crossover comparative study withethinyl oestradiol. Aust N Z J Obstet
56. Warren MP, Shantha S. Uses of progesteronein clinical practice. Int J Fertil Womens Med1999;44:96-103.
57. de Lignieres B, Dennerstein L,
BackstromT. Influence of route of administration onprogesterone
metabolism. Maturitas 1995;21:251-257.
58. Hermann AC, Nafziger AN, Victory J,
et al.Over-the-counter progesterone cream producessignificant drug
exposure compared to a food anddrug administration-approved oral
progesteroneproduct. J Clin Pharmacol 2005;45:614-619.
59. Pouly JL, Bassil S, Frydman R, et
al. Luteal phasesupport after vaginal progesterone: comparativestudy
with micronized oral progesterone.Contracept Fertil Sex
1997;25:596-601. [Article inFrench]
60. Mahesh VB, Brann DW, Hendry LB.
Diversemodes of action of progesterone and itsmetabolites. J Steroid
Biochem Mol Biol1996;56:209-219.
61. Dusterberg B, Nishino Y. Pharmacokinetic andpharmacological features of oestradiol valerate.Maturitas 1982;4:315-324.
62. McAuley JW, Kroboth FJ, Kroboth PD.
Oraladministration of micronized progesterone: areview and more
63. Burry KA, Patton PE, Hermsmeyer
K.Percutaneous absorption of progesterone inpostmenopausal women
treated with transdermalestrogen. Am J Obstet Gynecol
64. Mircioiu C, Perju A, Griu E, et
al.Pharmacokinetics of progesterone inpostmenopausal women: 2.
Pharmacokineticsfollowing percutaneous administration. Eur J DrugMetab
65. Mircioiu C, Perju A, Neagu A, et
al.Pharmacokinetics of progesterone inpostmenopausal women: 1.
Pharmacokineticsfollowing intravaginal administration. Eur J DrugMetab
66. Cicinelli E, Nahoul K, Sabatelli S,
et al.Administration of unmodified progesterone bynasal spray in
fertile women. Gynecol Endocrinol1995;9:289-293.67. Levy T, Gurevitch S,
Bar-Hava I, et al.Pharmacokinetics of natural
progesteroneadministered in the form of a vaginal tablet. HumReprod
68. Rylance PB, Brincat M, Lafferty K,
et al. Naturalprogesterone and antihypertensive action. Br Med J(Clin
Res Ed) 1985;290:13-14.
69. Armstrong JG. Hypotensive action of
progesteronein experimental and human hypertension. Proc SocExp Biol
70. Oelkers WK. Effects of estrogens
and progestogenson the renin-aldosterone system and blood
71. Elkik F, Mauvais-Jarvis P. The role
of progesteroneand progestins in hydroelectrolytic
metabolism(author’s transl). Nouv Presse Med 1980;9:35-38.[Article in
72. Tollan A, Oian P, Kjeldsen SE, et
al. Progesteronereduces sympathetic tone without changing
bloodpressure or fluid balance in men. Gynecol ObstetInvest
73. Molinari C, Battaglia A, Grossini
E, et al. Effectof progesterone on peripheral blood flow inprepubertal
female anesthetized pigs. J Vasc Res2001;38:569-577.
74. Tsuda K, Kinoshita Y, Nishio I.
Synergistic role ofprogesterone and nitric oxide in the regulation
ofmembrane fluidity of erythrocytes in humans: anelectron paramagnetic
resonance investigation. AmJ Hypertens 2002;15:702-708.
75. Toy JL, Davies JA, Hancock KW,
McNicol GP. Thecomparative effects of a synthetic and a
‘natural’oestrogen on the haemostatic mechanism in patientswith
primary amenorrhoea. Br J Obstet Gynaecol1978;85:359-362.
76. Orwoll ES, Stribrska L, Ramsey EE,
Keenan EJ.Androgen receptors in osteoblast-like cell lines.Calcif
Tissue Int 1991;49:183-187.
77. Stephenson K, Price C, Kurdowska A,
et al.Progesterone cream does not increase thromboticand inflammatory
factors in postmenopausalwomen. Blood 2004;104:16.
78. Cheng W, Lau OD, Abumrad NA.
Twoantiatherogenic effects of progesterone onhuman macrophages;
inhibition of cholesterylester synthesis and block of its
enhancementby glucocorticoids. J Clin Endocrinol Metab1999;84:265-271.
79. Fahraeus L, Larsson-Cohn U,
Wallentin L.L-norgestrel and progesterone have differentinfluences on
plasma lipoproteins. Eur J Clin Invest1983;13:447-453.
80. Ottosson UB. Oral progesterone and
estrogen/progestogen therapy. Effects of natural andsynthetic hormones
on subfractions of HDLcholesterol and liver proteins. Acta Obstet
GynecolScand Suppl 1984;127:1-37.
81. No authors listed. Effects of
estrogen or estrogen/progestin regimens on heart disease risk factorsin
postmenopausal women. The PostmenopausalEstrogen/Progestin
Interventions (PEPI) Trial.The Writing Group for the PEPI Trial.
82. Ottosson UB, Johansson BG, von
Schoultz B.Subfractions of high-density lipoprotein cholesterolduring
estrogen replacement therapy: a comparisonbetween progestogens and
natural progesterone.Am J Obstet Gynecol 1985;151:746-750.
83. Warren MP, Biller BM, Shangold MM. A
newclinical option for hormone replacement therapyin women with
secondary amenorrhea: effectsof cyclic administration of progesterone
fromthe sustained-release vaginal gel Crinone (4%and 8%) on
endometrial morphologic featuresand withdrawal bleeding. Am J Obstet
84. Williams JK, Honore EK, Washburn
SA, ClarksonTB. Effects of hormone replacement therapy onreactivity of
atherosclerotic coronary arteriesin cynomolgus monkeys. J Am Coll
85. Wagner JD, Martino MA, Jayo MJ, et
al. Theeffects of hormone replacement therapy oncarbohydrate
metabolism and cardiovascular riskfactors in surgically postmenopausal
cynomolgusmonkeys. Metabolism 1996;45:1254-1262.
86. Wallace JM, Shively CA, Clarkson
TB. Effects ofhormone replacement therapy and social stress onbody fat
distribution in surgically postmenopausalmonkeys. Int J Obes Relat
87. Beck P. Effect of progestins on glucose and lipidmetabolism. Ann N Y Acad Sci 1977;286:434-445.
88. Carmody BJ, Arora S, Wakefield MC,
et al.Progesterone inhibits human infragenicular arterialsmooth muscle
cell proliferation induced by highglucose and insulin concentrations. J
89. Lee WS, Harder JA, Yoshizumi M, et
al.Progesterone inhibits arterial smooth muscle cellproliferation. Nat
90. Minshall RD, Stanczyk FZ, Miyagawa
K, etal. Ovarian steroid protection against coronaryartery
hyperreactivity in rhesus monkeys. J ClinEndocrinol Metab
91. Miyagawa K, Rosch J, Stanczyk F,
HermsmeyerK. Medroxyprogesterone interferes with ovariansteroid
protection against coronary vasospasm. NatMed 1997;3:324-327.
92. Hermsmeyer RK, Mishra RG, Pavcnik
D, etal. Prevention of coronary hyperreactivity inpreatherogenic
menopausal rhesus monkeys bytransdermal progesterone. Arterioscler
ThrombVasc Biol 2004;24:955-961.
93. Otsuki M, Saito H, Xu X, et al.
Progesterone, butnot medroxyprogesterone, inhibits vascular
celladhesion molecule-1 expression in human vascularendothelial cells.
Arterioscler Thromb Vasc Biol2001;21:243-248.
94. Dubey RK, Gillespie DG, Jackson EK,
Keller PJ.17Beta-estradiol, its metabolites, and progesteroneinhibit
cardiac fibroblast growth. Hypertension1998;31:522-528.
95. Ottosson UB, Carlstrom K, Johansson
BG, vonSchoultz B. Estrogen induction of liver proteins
andhigh-density lipoprotein cholesterol: comparisonbetween estradiol
valerate and ethinyl estradiol.Gynecol Obstet Invest 1986;22:198-205.
96. Suvanto-Luukkonen E, Sundstrom H,
PenttinenJ, Kauppila A. Lipid effects of an intrauterinelevonorgestrel
device or oral vs. vaginal naturalprogesterone in post-menopausal
women treatedwith percutaneous estradiol. Arch Gynecol
97. Schairer C, Lubin J, Troisi R, et
al. Menopausalestrogen and estrogen-progestin replacementtherapy and
breast cancer risk. JAMA2000;283:485-491.
98. Mauvais-Jarvis P, Kuttenn F, Gompel
A,Benotmane A. Antiestrogen action of progesteronein the breast.
Pathol Biol (Paris) 1987;35:1081-1086. [Article in French]
99. Mauvais-Jarvis P, Kuttenn F, Gompel
A. Estradiol/progesterone interaction in normal and pathologicbreast
cells. Ann N Y Acad Sci 1986;464:152-167.
100. Gorins A, Denis C. Effects of
progesterone andprogestational hormones on the mammary gland.Arch Anat
Cytol Pathol 1995;43:28-35. [Article inFrench]
101. Inoh A, Kamiya K, Fujii Y, Yokoro
K. Protectiveeffects of progesterone and tamoxifen inestrogen-induced
mammary carcinogenesis inovariectomized W/Fu rats. Jpn J Cancer
102. Wren BG, Eden JA. Do progestogens
reduce therisk of breast cancer? A review of the evidence.Menopause J
North Am Menopause Soc 1996;3:4-12.
103. Cowan LD, Gordis L, Tonascia JA,
Jones GS.Breast cancer incidence in women with a historyof
progesterone deficiency. Am J Epidemiol1981;114:209-217.
104. Chang KJ, Lee TT, Linares-Cruz G,
et al.Influences of percutaneous administration ofestradiol and
progesterone on human breastepithelial cell cycle in vivo. Fertil
105. Formby B, Wiley TS. Progesterone
inhibits growthand induces apoptosis in breast cancer cells:inverse
effects on Bcl-2 and p53. Ann Clin Lab Sci1998;28:360-369.
106. Desreux J, Kebers F, Noel A, et
al. Progesteronereceptor activation – an alternative to SERMs inbreast
cancer. Eur J Cancer 2000;36:S90-S91.
107. Malet C, Spritzer P, Guillaumin D,
Kuttenn F.Progesterone effect on cell growth, ultrastructuralaspect
and estradiol receptors of normal humanbreast epithelial (HBE) cells in
culture. J SteroidBiochem Mol Biol 2000;73:171-181.
108. Plu-Bureau G, Le MG, Thalabard JC,
et al.Percutaneous progesterone use and risk of breastcancer: results
from a French cohort study ofpremenopausal women with benign breast
disease.Cancer Detect Prev 1999;23:290-296.
109. de Lignieres B, de Vathaire F,
Fournier S, et al.Combined hormone replacement therapy and riskof
breast cancer in a French cohort study of 3175women. Climacteric
110. Fournier A, Berrino F, Riboli E,
et al. Breast cancerrisk in relation to different types of
hormonereplacement therapy in the E3N-EPIC cohort. Int JCancer
111. Lemon HM, Wotiz HH, Parsons L,
MozdenPJ. Reduced estriol excretion in patients withbreast cancer
prior to endocrine therapy. JAMA1966;196:1128-1136.
112. Lemon HM. Pathophysiologic
considerations in thetreatment of menopausal patients with
oestrogens;the role of oestriol in the prevention of mammarycarcinoma.
Acta Endocrinol Suppl (Copenh)1980;233:17-27.
113. Lemon HM. Estriol prevention
ofmammary carcinoma induced by 7,12-dimethylbenzanthracene and
procarbazine. CancerRes 1975;35:1341-1353.
114. Lippert C, Seeger H, Mueck AO. The
effectof endogenous estradiol metabolites on theproliferation of
human breast cancer cells. Life Sci2003;72:877-883.
115. de Lignieres B. Oral micronized progesterone. ClinTher 1999;21:41-60;discussion 1-2.
116. Sitruk-Ware R, Bricaire C, De
Lignieres B, et al.Oral micronized progesterone.
Bioavailabilitypharmacokinetics, pharmacological andtherapeutic
implications – a review. Contraception1987;36:373-402.
117. Wilson KJ. Private communication.
118. Schiff I. The effects of progestins on vasomotorflushes. J Reprod Med 1982;27:498-502.
119. Leonetti HB, Longo S, Anasti JN.
Transdermalprogesterone cream for vasomotor symptomsand postmenopausal
bone loss. Obstet Gynecol1999;94:225-228.
120. Montplaisir J, Lorrain J, Denesle
R, Petit D. Sleepin menopause: differential effects of two formsof
hormone replacement therapy. Menopause2001;8:10-16.
121. Ryan N, Rosner A. Quality of life
and costsassociated with micronized progesterone
andmedroxyprogesterone acetate in hormonereplacement therapy for
nonhysterectomized,postmenopausal women. Clin Ther 2001;23:1099-1115.
122. van der Linden MC, Gerretsen G,
Brandhorst MS,et al. The effect of estriol on the cytology of
urethraand vagina in postmenopausal women with genitourinary symptoms.
Eur J Obstet Gynecol ReprodBiol 1993;51:29-33.
123. Heimer GM. Estriol in the postmenopause. ActaObstet Gynecol Scand Suppl 1987;139:1-23.
124. Takahashi M, Kushida K, Hoshino H,
et al.Biochemical markers of bone turnover do notdecline after
menopause in healthy women. Br JObstet Gynaecol 1999;106:427-431.
125. Bland R. Steroid hormone receptor expression andaction in bone. Clin Sci (Lond) 2000;98:217-240.
126. Liang M, Liao EY, Xu X, et al.
Effects ofprogesterone and 18-methyl levonorgestrel onosteoblastic
cells. Endocr Res 2003;29:483-501.
127. Barengolts EI, Gajardo HF, Rosol
TJ, et al. Effectsof progesterone on postovariectomy bone loss inaged
rats. J Bone Miner Res 1990;5:1143-1147.
128. Bowman BM, Miller SC. Elevated
progesteroneduring pseudopregnancy may prevent bone lossassociated
with low estrogen. J Bone Miner Res1996;11:15-21.
129. Fujimaki T, Kurabayashi T,
Yamamoto Y, et al.Effects of progesterone on the metabolism
ofcancellous bone in young oophorectomized rats. JObstet Gynaecol
130. Burnett CC, Reddi AH. Influence of
estrogen andprogesterone on matrix-induced endochondral
boneformation. Calcif Tissue Int 1983;35:609-614.
131. Ikram Z, Dulipsingh L, Prestwood
KM. Lackof effect of short-term micronized progesteroneon bone
turnover in postmenopausal women. JWomens Health Gend Based Med
132. Yamamoto Y, Kurabayashi T, Tojo Y,
et al. Effectsof progestins on the metabolism of cancellous bonein
aged oophorectomized rats. Bone 1998;22:533-537.
133. Wang C, Eyre DR, Clark R, et al.
Sublingualtestosterone replacement improves muscle massand strength,
decreases bone resorption, andincreases bone formation markers in
hypogonadalmen – a clinical research center study. J ClinEndocrinol
134. Baulieu E, Schumacher M.
Progesterone as aneuroactive neurosteroid, with special reference
tothe effect of progesterone on myelination. Steroids2000;65:605-612.
135. Gibson CL, Murphy SP. Progesterone
enhancesfunctional recovery after middle cerebral arteryocclusion in
male mice. J Cereb Blood Flow Metab2004;24:805-813.
136. Grossman KJ, Goss CW, Stein DG.
Effects ofprogesterone on the inflammatory response to braininjury in
the rat. Brain Res 2004;1008:29-39.
137. Schumacher M, Guennoun R, Robert
F, et al. Localsynthesis and dual actions of progesterone in
thenervous system: neuroprotection and myelination.Growth Horm IGF Res
138. de Moraes SA, Szklo M, Knopman D,
Park E.Prospective assessment of estrogen replacementtherapy and
cognitive functioning: atherosclerosisrisk in communities study. Am J
Source:Altern Med Rev.2006 Sep;11(3):208-23.