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The Necessity and Safety of Estradiol,
Progesterone and Testosterone
Restoration in Women
Estradiol, progesterone and testosterone are much more than “sex hormones”; they are required for
the function, growth, and maintenance of most tissues and organs in both women and in men. Estradiol
is the dominant hormone in women, but is almost completely lost at menopause. The menopausal
estradiol deficiency is natural, but is deleterious for a woman’s quality of life and long-term health.
Estradiol can be safely restored to optimal levels/effects if done so in the right way and with sufficient
progesterone and testosterone. Testosterone has similar benefits for women as for men, but to a lesser
extent due to their much lower levels. Unfortunately, women are being denied medically-necessary sexsteroid replacement due to medical ignorance. This failure to replace vital hormones is producing untold
suffering and causing thousands of unnecessary deaths every year in the United States alone.1
1. The Menstrual Cycle
In order to understand the female hormonal system, one must understand the menstrual cycle.
Whereas male sex-steroid hormone levels are stable over time, gradually declining with age, female
hormone levels vary markedly from week-to-week and with many conditions. The menstrual cycle exists
for the purpose of reproduction—to perpetuate the species. Only secondarily does it work to maintain a
woman’s well being and health. In fact the menstrual cycle and its disorders create many problems for
women’s quality of life and health. The ovaries produce three major sex steroids: estradiol,
progesterone, and testosterone; only the levels of estradiol and progesterone vary markedly during the
menstrual cycle. The ovaries contain follicles, nests of cells with a central egg surrounded by hormoneproducing granulosa and thecal cells. Hormone production is controlled by variations in the secretion of
follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gland. (See figure 1.) In
the follicular phase, FSH causes follicles in the ovary to ripen and produce estradiol. Estradiol causes the
lining of the uterus (endometrium) to thicken. A spike in FSH and LH output causes a single follicle to
release and egg. After ovulation, the follicle becomes the corpus luteum which produces large amounts
of progesterone. During the luteal phase, progesterone reduces proliferation in the uterine lining and
induces changes that are called “decidualization”. This prepares the endometrium to receive a fertilized
embryo. If no embryo implants itself into the endometrium, estradiol and progesterone production fall
and the uterine lining is sloughed, causing vaginal bleeding. Then the cycle starts all over again. Nature
“wants” women to get pregnant; the price for not doing so is the discomfort and inconvenience of
menstrual bleeding.
Figure 1 From http://www.multi-gyn.com/
Testosterone has little effect on the menstrual cycle and its levels do not vary much, except for a
peak at ovulation—well-timed to encourage intercourse.
2. Menopause is both Natural and Harmful
The ovaries are the only endocrine glands that are pre-programmed to fail at some point in life. This
failure occurs because women are born with a fixed number of follicles in their ovaries and they are lost
with every menstrual cycle and with aging itself. Even by age 30, estradiol and progesterone production
can decline or become irregular due to loss and aging of follicles. The follicles that were most healthy
responded to FSH/LH stimulation earlier. Eventually, no more follicles are left and the ovaries cease to
function. Whether the postmenopausal ovary produces any hormones is controversial. One study found
that it produced small amounts of estradiol and testosterone;2 another found no evidence of hormone
production.3
After menopause, most of the estradiol and testosterone in a woman’s body is produced from
adrenal DHEA and androstenedione in various tissues including fat, breast, bone and brain.4
Progesterone is always present in low levels in women and men as it is made by the adrenal glands. It is
made in large quantities only in women—after ovulation and during pregnancy. If a woman does not
ovulate, her progesterone levels stay low, similar to a man’s levels. The clinical effects of premenopausal
anovulation vary with how much estradiol is produced. A woman may have no bleeding, irregular
bleeding, and possibly very heavy bleeding. Anovulation occurs sporadically in healthy women, and is
quite common in the years just prior to menopause. The transition from regular, ovulatory menstrual
cycles to irregular bleeding and altered hormone levels prior to menopause is called “perimenopause”.
Once the ovaries cease to make estradiol and progesterone, the endometrium is not stimulated and
menses cease. The lack of any bleeding for one year in a woman over 45 is considered to be evidence of
menopause.
The major roles that estradiol and progesterone play in reproduction have blinded physicians to their
importance in human physiology. Estradiol, in particular, has hundreds of known actions, in most of the
Table 1. Estradiol Deficiency
Hot flashes
Irritability, insomnia, depression,
fatigue, aches
Poor memory, dementia
Atrophy of skin and connective tissue
Osteoporosis, fractures, loss of teeth
Genital atrophy, vaginal dryness
Incontinence
Endothelial dysfunction, hypertension
Atherosclerotic heart disease
Reduced insulin sensitivity
Increased body fat
tissues and organs of the body. It maintains the health of the
brain5, bones and skin,6,7 vagina, urinary tract, heart and
blood vessels. Estradiol deficiency causes hot flashes,
insomnia, fatigue, depression, vaginal dryness, urinary
incontinence, sexual dysfunction, bone fractures, heart
disease and dementia (See below.) After 5 years of
menopausal estradiol deficiency, both bone density and skin
collagen content have fallen by 25-30%.8 The skin has less
collagen, glycoaminoglycans and water content.9 Estradiol
deficiency increases the expression of a lipogenic gene,
causing an increase in body fat after menopause.10 All these problems can be prevented or reversed
with estradiol restoration. The loss of progesterone at menopause increases the risk of breast, uterine
and ovarian cancer. (See below.)
How is it possible that a natural event like menopause can be harmful? The answer lies in
understanding the evolution of the species. The female hormonal system exists to produce, breastfeed
and care for children; not to optimize women’s health, strength and stamina does the male hormonal
system. Women pay a high endocrine price for bearing the burden of reproduction, both pre- and
postmenopausally. They have many menstrual-cycle related symptoms and disorders. They have much
lower stamina and muscle strength because of their lower testosterone levels. They suffer from thyroid
and cortisol deficiencies much more than men. After menopause, they are left in a state of severe sexsteroid deficiency. Postmenopausal women have the same low progesterone levels as men very low
testosterone levels, and much lower estradiol levels than men of the same age! (See figure 2.) This
combined sex steroid deficiency has devastating effects upon their quality of life and long-term health.
Three of the primary causes of disability and death in women, cardiovascular disease (CVD),
osteoporosis and breast cancer, are all rare before menopause. All three are related to estradiolprogesterone-testosterone deficiency and imbalance. Bilateral oophorectomy before age 45 is
Female Sex Steroid Deficiency
pg/ml
8000
7000
6000
5000
4000
3000
2000
1000
0
Men
associated with a higher risk of death
Women
Testosterone
from all causes (RR 1.67).11 The
Progesterone
average
youthful
T
P
E
Young
Old
Young
Old
Figure 2. Menopausal sex steroid deficiency
0-31 pg/ml
Less
estrogen
than
old men!
(25-55 pg/ml)
female
estradiol-
progesterone-testosterone hormonal
milieu protects women from these
diseases. (See below).
Menopause is natural indeed, but
it is not good for women. It is not an
evolutionary adaptation to prolong a
woman’s well-being and survival; it is
an evolutionary accident. Our genetic heritage extends far back to the primate and hominid species that
preceded us. As mentioned before, the evolutionary adaptation of the species requires the death of
individuals. It was much more unlikely for our distant ancestors to survive to age 80 or 90 than it is for us
now. There was no evolutionary pressure for hominid and then human females to maintain their health
and quality of life for very long after age 50. The survival of our species required only that females were
able to produce, breastfeed, and raise to independence several children before they died.
The accidental nature of menopause is evidence by the reaction of the brain’s hypothalamic-pituitary
system. With either natural or surgical menopause, the pituitary starts to produce extremely high levels
of FSH to try to stimulate ovulation and hormone production. FSH and LH levels remain abnormally high
for the rest of a woman’s life. The brain continues to try to get the ovaries to function again, just as it
does with any other gland that fails. The brain was not programmed to accept menopause as “normal”
or good. Seen in this light, the bothersome early symptoms of menopause, like hot flashes and vaginal
dryness, are not just symptoms to be suppressed, but early warning signs of an endocrine deficiency
that will cause deterioration and death.
Testosterone is also essential to the health and well-being of women. Healthy young women have
free testosterone levels twice as high as their free estradiol levels. Testosterone has the same benefits in
women that is does in men, only to a lesser degree due to their lower levels. Even when high-normal,
women’s free testosterone levels are only about 1/10th those of men (ref. ranges: 0-2.2pg/ml for
women, 9-25pg/ml for men). Even in these lower amounts testosterone helps to maintain a woman’s
bone mass, muscle mass, stamina and sexuality. It improves her mood, mental function, and
assertiveness. Testosterone affects how a woman thinks and acts, and even what career she selects.
Higher testosterone levels are found in women in professional and managerial positions vs. housewives
and clerical workers. Women with higher testosterone levels identify themselves as independent,
strong, assertive, impulsive, resourceful, spontaneous, uninhibited, rational, patient and arguing.
Whereas, females with lower testosterone concentrations viewed themselves as civilized, socialized,
calm, quite, sentimental, shy, nice, sensitive, warmhearted, sympathetic, thoughtful, warm, practical
and kind.12 Lower testosterone and DHEAS levels are associated with low libido in pre- and
postmenopausal women.13,14
Testosterone levels are only part of a woman’s overall androgen status. As much as 70% of the
androgen effect in her body comes from the conversion of DHEA into testosterone with her cells. This is
only partly reflected in the serum testosterone level. About 50% of the testosterone in the blood is from
the ovaries; the other 50% is adrenal in origin, testosterone that has leaked into the blood from the
intracellular conversion of adrenal DHEA into testosterone. Thus adrenal DHEAS production is also very
important to a woman’s health and well-being. Women's testosterone levels drop by 50% between the
ages of 20 and 40 due to both reduced ovarian and adrenal androgen production.15,16 Many women in
their 40s and 50s are have extremely low testosterone levels, and their androgen deficiency is made
worse by estrogen replacement therapy which lowers DHEAS and testosterone levels by 25% and 45%
respectively.17,18 Birth control pills or patches lower DHEAS by 30% and free testosterone by 60%.19,20
The universal female androgen deficiency of aging is invisible to Reference Range Endocrinology. A
national laboratory has a "normal" range for total testosterone of 0-45ng/dL, and for free testosterone
0-2.2pg/ml. Other laboratories report ranges of 0-76ng/dL for total testosterone and 0.2-6.4mg/ml for
free testosterone. (A more careful study of healthy menstruating women at age 30 found a 95% free
testosterone range of 1.2 to 6.4pg/ml.21) As it stands, the lab report tells physicians that no detectable
testosterone is perfectly “normal”; so they conclude that women don’t need any testosterone.
3. Progesterone-Estradiol Complementarity
The female organs, the cyclic hormonal system and the act of reproduction itself all pose many
threats to a woman’s quality of life and health. In order to reproduce, the breast, uterine and ovarian
tissues must undergo a monthly cycle of proliferation and differentiation, and then breakdown if no
pregnancy occurs. Defects in this cycle can lead to many medical disorders and to cancers in the female
organs. Consider the historical context again. For a woman to have many years of menstrual cycles in
her life is a recent phenomenon. Throughout most of human history, women had unprotected sex from
adolescence until menopause. It is estimated that women had menstrual cycles for only 4 years of their
lives, on average. They were usually pregnant or breast feeding; both of these states are known to be
protective against the development of breast cancer.22 The exposure of the breasts to pregnancy levels
of estradiol and progesterone, even for a short time, causes a differentiation of the mammary ductal
Table 2. Progesterone Counteracts Estradiol
Decreases the synthesis of estradiol receptors
Increases the inactivation of estradiol
Reduces production of estradiol from estrone
Increases the sulfation of estradiol
Inhibits binding of estradiol to receptors
Inhibits production of estradiol by aromatization
epithelium that permanently reduces the risk of
breast cancer.23,24,25 Pregnancy also reduces
breast cancer incidence through its effect on
prolactin levels. Prolactin is a pituitary hormone
that stimulates breast proliferation in lactation.
Higher prolactin levels are associated with breast
cancer,26 and pregnancy reduces prolactin levels for a decade or more.27 Today, with abstention from
sex and with non-hormonal contraceptives, women postpone pregnancy for many years. They can have
menstrual cycles for 35 yrs. This puts them at much greater risk of breast, ovarian and uterine cancers,
endometriosis, polycystic ovary disease, ovarian cysts, premenstrual syndromes and many other
diseases and disorders.
During menstrual cycles, women need sufficient progesterone to balance estradiol in their breasts
and uterus. Estradiol stimulates the epithelial linings of the breasts uterine uterus, producing cellular
proliferation. Progesterone stops this proliferation and promotes maturation and differentiation of the
epithelial cells—preparing these organs for pregnancy. In the normal breast, estradiol stimulates growth
of the ductal system, while lobular development depends on progesterone. When cells differentiate
they become more specialized; they switch off certain genes and reproduce more slowly, making them
less likely to undergo malignant transformation. When no pregnancy occurs, the fall in estradiol and
progesterone levels leads to necrosis and sloughing of both the uterine lining and breast duct
epithelium.28 This may help to eliminate pre-cancerous cells.
Progesterone has many known anti-estradiol actions in the uterus and breasts.29 It decreases the
synthesis of estradiol receptors. It increases the conversion of estradiol to inactive estrone by inducing
17β-hydroxysteroid dehydrogenase Type 2. It reduces the conversion of inactive estrone to estradiol by
inhibiting 17β-hydroxysteroid dehydrogenase Type 1. It activates estradiol by increasing its sulfation.30
Progesterone also inhibits the binding of estradiol to its receptors.31 A metabolite of progesterone found
in breast tissue, 20alpha-dihydroprogesterone, inhibits the production of estradiol and estrone from
testosterone and androstenedione.32 A high progesterone/estradiol ratio in the luteal phase of normal
menstrual cycles helps to suppress proliferation and to prevent breast and uterine cancer. A low
progesterone/estradiol ratio is known as “luteal insufficiency” and produces a state of “estrogen
dominance” characterized by excessive breast fullness/tenderness, fluid retention and premature or
heavy menstrual bleeding and cramping.
Progesterone also has direct beneficial effects in the body. It helps to increase bone mass (see
below). It has a calming effect on the nervous system—reducing anxiety and improving sleep.
Progesterone has well-studied neuro-protective effects in the brain. It can reduce seizure susceptibility
through its conversion to neurosteroids such as allopregnanolone which enhance GABA(A) receptor
function and thereby inhibit neuronal excitability. 33 Progesterone also competes with aldosterone at
its receptors in the kidneys, producing a diuretic effect34,35 which counteracts estradiol’s fluid-retaining
effects.
Progesterone and estradiol production begin to decline around age 30. If there is no ovulation, no
progesterone is produced at all, putting a woman at greater risk of breast and uterine cancers and other
problems. During perimenopause when higher FSH levels are super-stimulating the ovaries, some
women can produce pregnancy-like estradiol levels and have very heavy, irregular bleeding. Many
hysterectomies are performed at this time, when all that is needed is high-dose progesterone
supplementation. Perimenopausal progesterone deficiency increases the initiation of breast and uterine
cancers.
A poetic way of thinking about estradiol in women is that it is both the “Angel of Life” and “Angel of
Death”. Estradiol is essential for both male and female health and to human reproduction, but it also
can cause disease and death in women—especially if not properly balanced with sufficient progesterone
and testosterone.
4. The Benefits and Safety of Estradiol-Progesterone-Testosterone
Restoration
Estradiol restoration is the only effective treatment for estradiol deficiency.36 Estradiol restoration
prevents and/or ameliorates all the symptoms and disorders listed table 1. (See Table 2.) Estradiol
restoration quickly eliminates hot flashes and improves sleep and mood. It restores vaginal moisture and
urogenital health. It improves psychological function.37 Estradiol protects brain cells from toxic injury,
and does progesterone.38 Estradiol increases serotonin production and urinary serotonin excretion39 and
relieves depression.40 It reduces body fat mass, intrapelvic fat, and intraperitoneal (belly) fat.41 It lowers
serum leptin and reduces waist-hip ratio.42 It improves the skin’s collagen content, thickness and
moisture.43,44
Progesterone supplementation is safe and any dose or level. It reduces proliferation in breast and
uterine tissue. Progesterone supplementation can treat any disorder of excess uterine bleeding or
cramping. Fibrocystic breast disease is associated with low luteal progesterone levels,45 and topical
progesterone is an effective treatment.46 We know little about the beneficial effects of progesterone on
the rest of the body in women and in men, this requires much more study.47 Oral micronized
progesterone improves sleep quality.48 Progesterone acts as a cortisol antagonist at the cortisol
receptor. Since excess cortisol promotes intrabdominal fat accumulation, sufficient progesterone can
Table 2. The Benefits of Estradiol
Restoration
Eliminates hot flashes
Improves sleep, mood and energy
Reduces achiness
Improves memory and mental clarity
prevents dementia
Slows and partially reverses atrophy
of skin and connective tissue
Builds bone, prevents fractures.
Restores vaginal moisture, sexual
function, and urogenital health
Dilates blood vessels, lowers blood
pressuer
Prevents atherosclerotic heart
disease
Improves insulin sensitivity
Reduces visceral (belly) fat
promote a more healthy fat distribution.49 In the sections
below, I will discuss the benefits of estradiol-progesterone
replacement for four diseases that cause most of the death
and disability in women: cardiovascular disease, breast
cancer, osteoporosis and dementia.
More specialists are becoming convinced that balanced
bioidentical
estradiol-progesterone
supplementation
provides all the expected health benefits without the risks
seen with non-bioidentical “HRT”.50,51,52,53,54,55,56,57,58,59 This
should be true by definition since BHRT simply restores a
more youthful, therefore healthier hormonal state.
However, there is a great deal of confusion about these
hormones and their effects, much of it due to the problems
caused by doctors using the wrong molecules and/or route of delivery. To understand the implications
of the many studies of HRT, one must understand the differences between the various bioidentical and
non-bioidentical molecules and the different effects of the different routes of administration (i.e., oral,
transdermal, vaginal, etc.). Many, if not most of the studies showing the benefits of menopausal HRT
used Premarin®, known generically as conjugated equine estrogens (CEE). CEE contains estradiol and
other estrogens that can be converted into estradiol or estradiol-like molecules. CEE raises estradiol
levels in women, correcting the deficiency. So one can assume that the quality-of-life and health
benefits obtained with CEE in studies are due to estradiol restoration. Conversely, all problems seen
with CEE and other non-biodentical hormone treatments are due to their altered chemical structure or
route of delivery until proven otherwise. I will use the term “estrogen” below to refer to studies that
included CEE. I will use the term “estradiol” if that was the only estrogen studied. In marked contrast to
the favorable risk/benefit profile of CEE, the various non-bioidentical progesterone-like molecules
(progestins, progestogens) do not produce the same benefits as progesterone and cause many serious
problems including increased risk of blood clots, strokes, heart attacks and breast cancer. (See Appendix
3.)
Testosterone must be included in menopausal hormone therapy to restore its youthful balance with
estradiol and progesterone. Testosterone maintains a woman’s health and improves muscle strength,
bone density, mood, energy, libido and sexual function.60 Testosterone reduces anxiety and general
fearfulness—which are much more common in women than in men precisely because women’s
Table 2. The Benefits of Testosterone
Restoration in Women
Improved energy and mood
Improved libido and sexual function
Reduction in anxiety
Greater physical stamina, endurance
Greater muscle mass and strength
Reduced subcutaneous fat
Better memory and mental clarity
Greater bone mass, less fracture risk
testosterone levels are so low. A single dose of
testosterone reduces fearfulness in women.61 Many
women tell me that they feel more “centered” on
testosterone. It can even allow them to do things that
they were afraid to do before. For some women the
reduction in fearfulness is ego-dystonic. With higher
testosterone levels they are not as afraid to express their
dislike or anger as they had been. They misinterpret there
new-found boldness as aggressiveness. Other women appreciate this benefit, especially if their work
requires bold thought and action. Testosterone supplementation improves mood and spatial cognition
in women with anorexia nervosa (who have low testosterone levels).62 Oophorectomized women
receiving both estrogen and testosterone feel more composed, elated, and energetic than those who are
given estrogen alone.63 Testosterone therapy alone in premenopausal women with low libido improves
well-being, mood, and sexual function.64 It is an effective treatment for hypoactive sexual desire
disorder.65 Adding testosterone to EP therapy improves sexual sensation and desire.66,67 Since
testosterone is aromatized to estradiol, testosterone implants alone in menopause can improve many
typical menopausal symptoms: psychological, somatic and urogenital.68 The benefits of testosterone on
sexual function are not due to its aromatization to estradiol.69 The addition of testosterone to estrogen
therapy in oophorectomized women improves energy, well-being, and appetite and reduces somatic,
psychological, and menopausal symptoms.70 Testosterone injections given to women on ERT improve
sexual function, lean body mass, and muscle strength.71 Testosterone and estradiol implants in equal
amounts (50mg/3mos) produce marked improvements in bone mass, fat-free (muscle) mass, and sexual
function.72 Transdermal testosterone therapy in hypopituitary women increases muscle size, bone
density, mood and sexual function.73 With testosterone supplementation, women are often very happy
to find that they can gain some muscle size and strength when working out at the gym. They have
greater physical stamina. They are able to do household tasks with greater ease; even simple things like
opening a large door are easier. This greater muscle strength and size combats the frailty that comes
with advanced age.
Testosterone restoration is safe. Not only does testosterone appear completely safe at female
physiological doses,74 as one would expect, but even giving women male levels of testosterone (in
female-to-male transsexuals) for many years is not associated with any increase mortality, breast cancer,
vascular disease, or other major health problems. 75,76 No significant increase in the risk of cardiovascular
diseases or breast cancer had been found in women using testosterone (implants, tablets, or injections); the
only risks are its androgenic effects (hirsutism, acne, clitoromegaly, etc.).77 These problems are dose-related
and women vary greatly in their susceptibility to them. Some women are genetically predisposed to have
more facial hair, or instance, and will not tolerate testosterone supplementation for this reason. Others have
very little tendency towards facial hair or acne, even at high testosterone doses. Testosterone’s effects
operate on a continuum, and each women must choose her own compromise. They benefit in many ways
from higher levels, but at some point the increase in body hair or pimples will become unacceptable and the
dose should be lowered.
Hormones and Breast Cancer
Breast cancer, like all cancers, occurs due to a genetic mutation, or number of mutations in the cells
of a tissue or organ. Hormones do not cause genetic mutations, they do not cause cancer. However,
hormones can play a facultative, enabling
Micheli A, Ordet Study: Int. J. Cancer 112 (2004) (2), pp. 312–318.
Progesterone vs. Breast Cancer
role in sex organ cancers. Higher levels of a
hormone
or
hormone-like
drug
that
stimulate a tissue to proliferate increase the
6,000 women
5 yr. F/U
likelihood that a mutated cell line will be
produced and then will grow faster,
avoiding the immune system that could
eliminate it. With such stimulation, existing
tumors will be detected earlier—leading to
Higher luteal progesterone=lower risk of breast cancer
See also: Sturgeon SR Cancer Causes Control. 2004 Feb;15(1):45-53.
a higher incidence of diagnosis during
treatment in studies. Even short treatment
periods with stimulating hormones/drugs can cause an increase in breast cancer diagnosis.78 This is the
true meaning of studies that reveal an “increased risk of breast cancer” with hormonal treatments. It is
an increase in diagnosis of breast cancer. The cancers themselves were most likely present for several
years or more before becoming detectable.
Mainstream medical organizations hold that both estradiol and progesterone promote breast cancer.
It is true that estradiol stimulates cell proliferation in the uterus and the breasts. Unopposed estradiol
(with no progesterone) is known to increase uterine cancer risk. This is why conventional
(pharmaceutical) HRT guidelines require that progesterone or a progesterone-like drug (“progestin”) be
included with any estrogen therapy in a woman with a uterus. Unopposed estradiol has the same effect
in the breast, stimulating cellular proliferation and thus facilitating the initiation and growth of breast
cancers. In the breast as in the uterus, progesterone reduces cellular proliferation and thus the risk of
clinical breast cancer. Fibrocystic breast disease has been associated with higher estradiol and lower
progesterone levels,79,80,81 and with evidence of progesterone resistance.82 Longer menstrual cycles, a
sign of higher luteal phase progesterone levels, are associated with a lower risk of breast cancer.83
Higher body mass index in menopause increases the risk of breast cancer, most likely though an increase
in bioavailable estradiol in the absence of progesterone.84 Higher bone density in menopause is
associated with higher breast cancer risk—this relationship is explained by higher estradiol levels.85 In
premenopausal women, breast cancer has been repeatedly associated with higher estradiol and lower
progesterone levels during the luteal phase.86,87,88, Some studies do not show a correlation with higher
estradiol levels, but with higher testosterone levels,89 particularly when combined with low
progesterone.90
Dr. John Lee was the first person to argue publicly that breast cancer and many other female health
problems were due to "estrogen dominance"—an excess of estradiol effect caused by a relative lack of
progesterone.91 Many other researchers now agree with the theory that progesterone insufficiency
increases the risk of breast cancer.92,93 The effects of progesterone on breast tissue have been studied
extensively in vivo and in vitro, and are consistent with progesterone’s known direct effects and its antiestradiol effects. Progesterone cream applied to female breasts eliminates the proliferative-mitotic
effect of estradiol as seen in breast biopsies.94,95,96 Applying progesterone to the breasts lowers the risk
of breast cancer (RR 0.8).97 In both normal breast epithelial cells and cancer cells, estradiol increases
proliferation
while
progesterone
decreases
proliferation
and
induces
apoptosis
(cell
death).98,99,100,101,102,103 Transdermal estradiol given with cyclical (2 weeks per month) oral progesterone
did not increase cellular proliferation or increase breast density.104
Progesterone’s protective effect against breast cancer has been seen in large, multi-year studies.
Higher luteal phase progesterone levels were associated with a much lower risk (RR 0.12) of breast
cancer diagnosis over the next 5 yrs (see figure 8.).105 Premenopausal women with low luteal
progesterone levels were found to have 5.4x higher risk of early breast cancer.106 Progesterone’s
protective effect has also been seen in several studies of HRT. In most countries, a progestin is
prescribed to women with a uterus; only in France is progesterone in common use, generally with
transdermal estradiol. The E3N-EPIC study in Europe found that postmenopausal women who took
transdermal estradiol alone had a 20% increase in breast cancer diagnosis over women not taking any
hormones. This is to be expected given unopposed estradiol’s stimulatory effects in the breasts. Women
who took progesterone along with transdermal estradiol (because they had a uterus) had instead a
reduction in the incidence of breast cancer (RR-0.9).107 In a longer follow up with more patients in the
same study, the RR increased to 1.0 (no increased risk).108 Similarly, a large cohort study in France found
no increase in breast cancer incidence in
E3N-EPIC Study
TD-E2=transdermal estradiol
Cohort study
55,000 women
8 years f/u
women on HRT, most of whom were
taking
transdermal
estradiol
and
progesterone.109 A case-control study in
France
estradiol
found
and
that
women
taking
progesterone
were
protected against breast cancer relative
to never users of HRT (RR=0.8).110 The
MISSION study in France also found a
Int J Cancer. 2005 Apr 10;114(3):448-54
E2 plus progesterone decreased risk of breast cancer!
See also: De Lignieres B, de Vathaire F, Fournier S, et al. Combined hormone replacement therapy and risk of
breast cancer in a French cohort study of 3175 women. Climacteric 2002;5:332–40.
reduction in breast cancer for women
taking
estradiol
and
progesterone
(RR=0.4).111 Most women in the taking
progesterone in these studies received one 100mg oral capsule daily. This dose and route are relatively
ineffective. (See below.) It is likely that a higher effective dose of progesterone would produce a greater
decrease in breast cancer diagnosis risk compared to no hormone replacement.
Based on such evidence, a European research group concluded that progesterone has antiproliferative effects in the female breast, and could thereby potentially reduce the risk of breast
cancer.112 Another group stated, “The hypothesis of progesterone and some progesterone-like
progestins decreasing the proliferative effect of estradiol in the postmenopausal breast remains highly
plausible and (progesterone) should be…the first choice for symptomatic postmenopausal women.”113 In
the next chapter I will explain why the anti-proliferative, anti-cancer effects of progesterone are not
known or discussed in the United States.
The Key - Intrammamary Estradiol Production
The demographics of breast cancer give us more clues to its hormonal influences. The incidence of
breast cancer diagnosis begins to rise after age 30, when progesterone production begins to decline, and
continues to rise long after menopause (see figure 6.). The fall-off in diagnosis after age 80 is due to
reduced screening and/or diagnostic evaluations after that age. It usually takes 5 to 10 yrs. for a breast
cancer to grow from one cell to a detectable mass (~1cm). So the initiation of breast cancers continues
to increase long after menopause, after both progesterone and estradiol have fallen to low levels in the
blood. The same pattern is seen in uterine
Breast Cancer Rate vs. Age
Loss of progesteronehigher risk of breast cancer
Menopause
Ovarian function
cancer, which is known to be due to
perimenopausal
and
menopausal
progesterone deficiency. (fig 6.). Ovarian
cancer also appears to be promoted by
estradiol
and
prevented
by
progesterone.114,115,116 It is well-known
that
anti-estradiol
tamoxifen
and
treatments
aromatase
like
inhibitors
reduce breast cancer diagnosis and
National Cancer Institute. SEER cancer statistics review 1975-2002. Table IV-3.
recurrence in 5 to 10 yr. follow-ups.
An explanation for this continued rise in breast cancer diagnosis throughout menopause and efficacy
of anti-estradiol treatment was suggested
Uterine Cancer Rate vs. Age
Menopause
by two recent studies. The first examined
fluid aspirated from the nipples of pre- and
postmenopausal women. It found no
decrease in the amount of estradiol in the
breasts in menopause. Postmenopausal
Ovarian function
Progesterone levels
women had as much estradiol in their
breasts as premenopausal women.117 This
is possible because breast tissue can
produce
Cancer Research UK 2006
estrone
locally
from
androstenedione, an androgen produced
from adrenal DHEA. Estrone can be
converted into estradiol. A probable explanation for the breasts’ ability to produce estradiol is lactation.
During breastfeeding a woman’s serum estradiol level remains quite low because the menstrual cycle is
suppressed. Estradiol deficiency symptoms like vaginal dryness can occur. During this time, the breasts
may require more estradiol than is available from the serum in order to maintain milk production.
Intramammary estradiol production may also have been an evolutionary adaptation to allow women to
continue to breastfeed children when stress or starvation has caused their menses to stop. It allows
even postmenopausal women to lactate.
This creates a problem in the breast. While the postmenopausal breast has youthful estradiol levels,
it has no progesterone. Progesterone cannot be produced within the breasts, it must come from the
circulation.118 The breasts actually concentrate progesterone to levels 3-4 times higher than in the
serum.119 The post-menopausal breast is in a state of estrogen dominance that can only be corrected by
sufficient progesterone supplementation. This lack of intramammary progesterone is a sufficient
explanation for why breast cancer incidence continues to rise long after menopause, and for why the
majority of breast cancers occur after menopause, in spite of the fact that estradiol levels in the serum
are very low. It would be interesting to see the results of long-term trials of progesterone-only
supplementation in perimenopause and menopause to prevent breast cancer. However it would be
unethical to deprive any woman of necessary estradiol supplementation; and because of its antiestradiol effects, progesterone supplementation can worsen symptoms of estradiol deficiency.
Testosterone, DHEA and Breast Cancer
The associations of higher estradiol and lower progesterone with breast cancer are strong. What
about the androgens, testosterone and DHEA? Their effect on breast cancer risk is much more
complicated and depends upon the estradiol-progesterone status of the woman. Higher testosterone
levels in menopause have been related to breast cancer, but this association may be indirect as higher
testosterone levels reduce SHBG levels and thereby increase free estradiol levels.120 Some studies show
increased breast cancer risk in premenopausal women with higher testosterone levels,121 and especially
with higher testosterone and lower progesterone levels.122 The combination of higher testosterone and
low progesterone levels in a premenopausal woman may increase breast cancer risk by a factor of 90.123
Again, the key appears to be progesterone. The usual cause of higher testosterone levels in
premenopausal women is polycystic ovary syndrome (PCOS) and its subclinical forms. Women with
PCOS have some degree of insulin resistance. Higher insulin levels disturb ovarian function, causing
anovulation and increasing testosterone production by the ovaries. Higher insulin levels directly increase
the risk of breast cancer.124 Since women with PCOS do not ovulate, or ovulate rarely, they have low
progesterone levels which predispose them to breast cancer. Thus the presence of PCOS of all degrees
in the population may be a sufficient explanation for the correlations found between higher
premenopausal testosterone levels and breast cancer.125
In women with low estradiol levels, more testosterone can increase serum estradiol levels through its
aromatization into estradiol, and by decreasing SHBG levels and thereby increasing free estradiol levles.
However, In the normal premenopausal state of estradiol sufficiency, testosterone opposes estradiol’s
proliferative effects in the breast.126,127 Regular testosterone injections given to female-to-male
transsexuals cause breast atrophy, with a marked reduction in glandular tissue.128,129 This occurs even
though their estradiol levels are not greatly reduced compared to normal follicular-phase levels. In
breast cancer cells, testosterone and its potent metabolite dihydrotestosterone (DHT) oppose estradiolinduced stimulation.130,131,132 The addition of testosterone to estrogen/progestin therapy in menopause
reduces proliferation in the breast133 and reduces breast cancer incidence to that of non-users of HRT.134
Testosterone is also an effective treatment for breast cancer.135,136 Thus the majority of the evidence
indicates that testosterone supplementation does not increase breast cancer risk in estradiol-replete
women.137 Menopausal BHRT should include testosterone in order to reduce breast cancer risk or
recurrence,138 not to mention to improve a woman’s health and quality-of-life.
DHEA can be converted throughout the body, and within the breasts into both estrogens and
androgens. This may account for the conficting reports of DHEA levels and breast cancer. Most studies
and reviews, but not all,139 have associated lower levels of DHEAS and its metabolites with increased
breast cancer risk in premenopausal women.140,141,142,143 In postmenopausal women there seems to be
either no correlation between DHEAS levels and breast cancer,144,145 or a positive correlation (increased
risk with higher DHEAS levels).146,147 What do cell studies show? DHEA administered to androgenreceptor-positive breast cancer cells reduces proliferation and induces apoptosis.148 DHEA reduces
mammary carcinogenesis in rats.149 Perhaps, overall, with all other hormonal factors being equal, the
natural decline in DHEAS with age tends to promote breast cancer. The effect of DHEA on breast cancer
also depends upon a woman’s estradiol and progesterone levels. Overall, DHEA supplementation to
restore youthful female levels may help prevent breast cancer, when combined with appropriate
estradiol, progesterone and testosterone supplementation.
BRCA Gene-Variants Associated with Progesterone and Testosterone Resistance
Progesterone resistance has been associated with breast cancer 150 and uterine cancer. 151 The
BRCA 1 and 2 gene variants that increase the risk of breast cancer have been found to produce
progesterone resistance. They inhibit the activity of the progesterone receptor and of gene expression
related to progesterone action.152 BRCA1 and BRCA2 carriers often do not make progesterone-receptor
B (PRB).153 In breast cancer cells, BRCA1 downregulates the expression of PRA and/or PRB.154,155 The
normal BRCA1 gene is also a co-activator of the androgen receptor in normal breast cells. Women
with BRCA1 mutations (reduced functional BRCA1 protein), have less efficient androgen receptors.
There is reduced androgen-mediated growth inhibition of breast epithelial cells and tumors develop
more rapidly.156,157 Women with both the BRCA1 gene variant and abnormalities of the androgen
receptor gene have a higher risk of breast cancer.158 It is possible that sufficient progesterone and
testosterone supplementation would reduce the cancer risk with BRCA mutations to baseline.
Cortisol and Thyroid
Cortisol opposes estradiol’s stimulatory effects in the uterus159 I have seen cortisol supplementation
reduce uterine bleeding/cramping and the symptoms of endometriosis. I have also seen it reduce breast
fullness and tenderness in women. I have also frequently diagnosed cortisol deficiency in women with a
history of breast or uterine cancer. This possible connection requires further study. Low thyroid
hormone levels and thyroid autoimmunity have also been associated with breast cancer160,161,162,163 and
its recurrence.164
Vitamin D, Iodine and Breast Cancer
Vitamin D is also a hormone; it should actually be called “Hormone D”. Breast cancer incidence is
reduced in women with greater sun exposure.165,166 Breast cancer, particularly aggressive breast cancer
has
been
associated
with
lower
levels
of
Vit.
D,
especially
in
postmenopausal
women.167,168,169,170,171,172,173,174,175
Vitamin D Prevents Breast Cancer
Higher levels of Vit. D have also been
associated with improved breast
cancer survival.176,177,178 Vitamin D
and calcium supplementation lowers
the incidence of breast cancer.179 A
good target for Vitamin D sufficiency
is a 25-OH Vitamin D level of 50 to
60ng/ml. For persons not receiving
much
sunlight,
this
generally
requires 1500IU/day in infants, 2000IU/day in children ages 1-12, and 4000IU daily for adults. Higher
doses can be taken under medical supervision to obtain target serum levels. Some persons require
20,000IU daily to maintain optimal Vitamin D levels.
Iodine sufficiency is necessary for normal breast architecture and health, and iodine supplementation
may help treat fibrocystic breast disease and prevent breast cancer.180,181,182,183,184,185
BHRT after Breast Cancer
What about women with who have been diagnosed with breast cancer? The standard “hormonal
therapy” for estradiol-receptor-positive breast cancer at this time is complete estradiol deprivation. For
women with estradiol-receptor-negative breast cancer, estradiol replacement should not be
contraindicated at all, however most physicians discourage it out of fear of being blamed for a
recurrence. (See “Corrupting effect of the legal system” in chapter 2.) Due to the breast-cancerpromoting effects of unopposed estradiol and most progestins, they inappropriately believe that
hormone replacement of any kind is will promote breast cancer and cause other health problems. (See
chapter 6.) Estradiol deprivation is accomplished either with an estrogen blocker, tamoxifen, in women
who are premenopausal, or with an aromatase inhibitor in postmenopausal women. The latter prevents
them from making estradiol from testosterone and DHEA. As the growth and reproduction of estradiolreceptor-positive cancer cells is partially dependent upon estradiol, estradiol deprivation does slow their
proliferation temporarily. Thus the 5 and 10 year recurrence/survival rates are improved slightly with
these therapies. However, they do not cure the cancer. It will recur if still present in the body, often in a
more aggressive form as a result of hormone deprivation. (For an excellent review of the real effects of
breast cancer diagnosis and treatment see this review.186). On the other hand, estradiol-deprivation
therapies have devastating effects on a woman’s quality of life and overall health. They cause all the
symptoms and medical disorders seen with surgical or natural menopause.187,188 Many women do not
take these drugs for the recommended time due to their symptoms.
Breast cancer cells with estradiol and/or progesterone receptors are more normal than receptornegative cells, and thus are associated with better survival. Progesterone-receptor-positivity is most
strongly associated with longer survival,189,190 and given progesterone’s known anti-proliferative, anticancer effects in the breast, receptor-positivity provides an opportunity to treat breast cancer with
progesterone supplementation.
Most people want to feel and function well in the time they have left, not to live a little longer but in
misery the entire time. Can postmenopausal women who have been diagnosed with breast cancer
improve their quality of life and other aspects of their health by replacing estradiol, progesterone and
testosterone? Without seriously reducing the length of their life? Many feel so much better on BHRT
that they say they would continue it even if they know they would live a few less years. They certainly
have the right to choose to replace their hormones. What does the evidence say about this choice?
There have been many observational studies of non-bioidentical estrogen and estrogen/progestin
replacement after breast cancer. Most studies and reviews have found either no increase or a reduction
in
breast
cancer
recurrence
with
estrogen-only191,192,193
and
estrogen-progestin
treatment.194,195,196,197,198,199 Only one study has shown an increase in breast cancer recurrence events.200
It involved estradiol+norethisterone, a combination which has been shown to have proliferative effects
in the breast201 and to increase the risk of initial breast cancer diagnosis.
So the majority of studies show no increase in recurrence even when women use non-biodentical
progestins that are known to increase breast tissue proliferation. Unfortunately, there have been few
studies of estradiol and progesterone replacement after breast cancer diagnosis, and none with
estradiol, progesterone and testosterone replacement. Two studies were done with rats. Estradiol and
progesterone treatment helped prevent and cure breast cancer in rats after exposure to a carcinogen.202
Progesterone was found to be as effective as tamoxifen in preventing estrogen-induced mammary
tumors in rats.203 In the one human study, estradiol with progesterone had a beneficial effect in
advanced breast cancer.204 I believe that it is probable that progesterone-only and combined estradiolprogesterone-testosterone therapy will reduce breast cancer recurrence rates while restoring health
and quality of life. In summary, the evidence regarding hormones and breast cancer shows that:





Estradiol-only supplementation promotes breast cancer.
Progesterone supplementation prevents breast cancer.
Estradiol combined with sufficient progesterone prevents breast cancer.
Testosterone supplementation prevents breast cancer in estradiol-replete women.
Estradiol-progesterone-testosterone supplementation is not contraindicated in breast cancer,
and may be therapeutic.
Sex Steroids and Cardiovascular Disease
When it comes to heart disease, estradiol has two effects that must be considered. It prevents
atherosclerosis—the formation of plaques in the walls of large arteries. So it lowers the long-term risk of
coronary heart disease and stroke. However in the short run, estradiol replacement, especially oral
estradiol, increases a woman’s blood-clotting tendency. This can cause thrombotic events (deep vein
thrombois, heart attack, and stroke) in susceptible women who have an underlying pro-clotting
tendency. (factor V Leiden, prothrombin gene mutation, or deficiencies of antithrombin, protein C, or
protein S, etc.) (See Route of Delivery below.)
It is well known that the youthful female hormonal milieu is highly protective against cardiovascular
disease, particularly against the atherosclerotic process in the coronary arteries that leads to heart
attacks. Heart attacks are usually caused
Coronary Heart Disease vs. Age
by a blood clot forming on an unstable
atherosclerotic plaque. Heart attacks are
Female Risk
Menopause
Ovarian Function
rare in premenopausal women, but after
menopause women’s rate of coronary
heart disease (CHD) rises faster than
men’s. CHD includes heart attacks,
angina, and other problems due to
atherosclerosis in the coronary arteries.
AIHW Heart, stroke and vascular diseases - Australian facts 2004.
(See Figure 8) Women have a higher risk
of CHD than men after age 65, and higher mortality after age 70!205 This increased risk after menopause
is clearly due to the loss of sex steroids, especially estradiol. Premenopausal and perimenopausal
women with lower estradiol levels have a higher incidence of CHD.206 They have a more rapid
progression of carotid artery atherosclerosis,207 which is slowed by estradiol replacement therapy.208,209
Premature ovarian failure causes endothelial dysfunction (an early indicator of athersoclerosis) that can
be corrected by 6 months of estrogen therapy.210 Surgical oophorectomy (removal of the ovaries) is
associated with 2 to 7 times greater risk of heart attack, and the earlier the ovaries are removed, the
greater the risk.211,212,213 Estrogen replacement can eliminate this excess risk.214 Surgical oophorectomy is
more deleterious than natural menopause because the postmenopausal ovary continues to make small
amounts of estradiol and testosterone. So the removal of the ovaries, even at the usual time of
menopause, produces a higher risk of CHD and hip fracture.215 Needless to say, any woman who has her
ovaries removed should immediately start to replace the hormones that she has lost—estradiol,
progesterone and testosterone.
Estradiol is known to counteract the atherosclerotic process by many mechanisms.216 Estradiol
maintains the health and function of the endothelium—the lining of our blood vessels.217 It activates
endothelial nitric oxide synthase, leading to arterial vasodilation. In the longer-term it modulates the
vascular response to injury and atherosclerosis.218 Long-term oral CEE therapy in menopause was found
to reduce risk of heart disease in many observational and case-control studies219,220,221 Estrogen
replacement reduces coronary artery atherosclerotic plaque size and progression with age.222
Transdermal estradiol replacement has beneficial effects on vascular function and CHD risk markers,223
and is associated with a 40% reduction in risk of heart attack.224 Estradiol restoration lowers blood
pressure225,226 and LDL cholesterol levels.227 Transdermal estradiol markedly improves insulin
sensitivity,228 and lower insulin levels help prevent hypertension and atherosclerosis.
Progesterone does not counteract estradiol’s beneficial
Estradiol vs. Cardiovascular
Disease
Prevents the oxidation of LDL
Improves lipid profile
Reduces lipoprotein (a)
Reduces blood pressure
Improves endothelial function
Dilates arteries
Lowers blood pressure
Reduces plaque formation
Improves insulin sensitivity
cardiovascular effects, and adds additional benefits. In surgically
menopausal
monkeys,
estradiol-progesterone
replacement
reduced the accumulation of LDL in the coronary arteries by
70%.229 Oral estradiol and progesterone improve peripheral blood
flow in women.230 Progesterone decreases proliferation of vascular
smooth muscle cells caused by high blood glucose and insulin
levels.231 Progesterone reduces coronary artery hyperreactivity
and vasoconstriction in monkeys232 and enhances coronary blood
flow in women with ischemia.233 Progesterone supplementation alone lowers blood pressure234 and the
blood pressure response to stress.235
In women with a history of CAD, and thus established atherosclerosis and at higher risk for a
myocardial infarction, oral estradiol did not affect subsequent cardiac events, but did lower overall
mortality.236 Only one study found that transdermal estradiol was associated with a small increase in
cardiac events, in the first two years,237 consistent with the slight pro-thrombotic effect of higher
estradiol levels, which can be significant in women with an underlying thrombotic tendency. Any small
increase in thrombotic events with initiating estradiol replacement in women with CAD must be
weighed against all the long-term benefits including slowing the progression of their atherosclerotic
disease.
Deficiencies of testosterone and other androgens play a role in menopausal heart disease also.
Women with CAD have lower free testosterone levels.238 In postmenopausal diabetic women, lower
free testosterone was associated with increased cardiovascular and all-cause mortality.239
Postmenopausal women with lower testosterone levels have more coronary atherosclerosis at
angiography.240 Postmenopausal women with higher testosterone levels have better flow-mediated
arterial dilation.241 Women who suffer heart attack or stroke have lower androstenedione levels, a weak
androgen made from DHEA that can be converted into testosterone, and those on HRT have lower
testosterone levels than controls.242 Lower DHEAS levels are associated with stroke in women.243
Postmenopausal women with CAD have lower DHEAS levels.244 Testosterone replacement improves
insulin sensitivity.245
Women with CHD (MI, stroke) who were taking estrogen-progestin therapy had lower testosterone
levels than matched controls.246 Testosterone therapy added to estrogen therapy increased flowmediated arterial dilation.247 The favorable changes seen in women’s lipid profiles with estradiol alone
are not altered by the addition of testosterone.248 Women given testosterone injections in various doses
producing serum testosterone levels up to 232ng/dl (low in the male reference range) did not have any
significant deleterious changes in fasting glucose, fasting insulin, insulin resistance, C-reactive
protein, adiponectin, blood pressure, or heart rate.249 No increase in morbidity or mortality has been
seen in female-to-male transsexuals (women given high-normal male levels of testosterone by
injections).250 If male levels cause no health problems, surely lesser levels of testosterone in women will
produce no harm.
There are many studies done in women that correlate higher testosterone levels with poor CHD
outcomes, but these are contaminated by patients with Polycystic Ovary Syndrome (PCOS). This disorder
is due in most cases to insulin resistance—a pre-diabetic condition. Insulin resistance rises with
overweight and obesity. Most women with PCOS are overweight. The higher insulin levels interfere with
ovarian hormone production, causing the ovaries to make more testosterone, less estradiol, and no
progesterone. Menstrual cycles become infrequent or stop altogether. The negative health effects of
PCOS are caused by the obesity and high insulin levels. The elevated testosterone levels are just another
consequence of the pathological processes at work.
In summary, the evidence regarding estradiol and progesterone and cardiovascular disease shows
that:





Youthful female estradiol, progesterone and testosterone levels are protective against
atherosclerotic disease.
Oral and transdermal estradiol replacement reduce atherosclerosis and heart disease risk in the
long term.
Oral estrogens, much more than transdermal estradiol, greatly increase the risk of thrombi in
susceptible women in the first 2 years of therapy (DVT, stroke, heart attack)
Progesterone does not counteract the beneficial effects of estradiol and has additional
cardiovascular benefits.
Testosterone replacement therapy, even when superphysiological for women, does not increase
the risk of CHD or death.
Osteoporosis
Osteoporosis is very common in menopause, and it is due almost entirely to sex-steroid deficiency,
especially estradiol deficiency. Bone is a living tissue; old bone is being constantly reabsorbed by
osteoclasts and new bone laid down by
osteoblasts.251 Estradiol inhibits osteoclastic
activity, 252 slowing resorption of old bone while
testosterone
and
progesterone
stimulate
osteoblastic activity, building new bone. Bone
loss in women actually begins long before
menopause, around age 30, due to declining
sex steroid and growth hormone levels. After
menopause, women lose 25% of their bone
mass in first 5 years. By 20 yrs. after
30
Speroff L, Fritz M Clinical Gynecologic Endocrinology and Fertility,
menopause they have a 50% reduction in
7 th
Ed.
trabecular bone, 30% reduction in cortical
bone. 50% of women age 65 and older have spinal compression fractures. A 50 yr. old woman has a 14%
lifetime risk of hip fracture, and after the age of 80 her lifetime risk is 30%.253 Early menopause (before
age 47) is associated with a higher risk of osteoporosis, fractures and death by age 77.254
Greater bone loss is in premenopausal women with lower testosterone levels255 and in
perimenopausal women with lower estradiol and testosterone levels.256 Women who do not ovulate
due to strenuous physical activity have lower estradiol and progesterone levels and thus lose bone
mass.257 In postmenopausal women, lower bioavailable testosterone, not estradiol levels are associated
with hip fracture.258 Women with the highest bioavailable testosterone had almost no height loss over
16 yrs, compared to 10cm loss for those with the lowest bioavailable testosterone. (See figure 15.)259
Postmenopausal women with vertebral crush fractures had androstenedione and testosterone
production rates that were one-half those of women without such fractures, but no difference in
estradiol production rates.260
Hormone replacement restores bone health—it increases bone density while preserving normal
osteoclast-osteoblast bone remodeling. Perimenopausal and postmenopausal bone loss is preventable
by EPT therapy begun immediately when estradiol
is deficient. Progesterone and testosterone may
be started before the onset of estradiol
deficiency.
Long-term CEE therapy reduces osteoporotic
fracture risk in half and maintains much higher
bone density.261 Much better results can be
expected with long-term optimal estradiol,
progesterone and testosterone replacement.
Bone density increases by 4 to 8% in 1 year with
estradiol replacement,262 4% in 9 months of oral
CEE.263 Collagen cross-linking and strength also
increases with estradiol replacement,264 which
improves bone strength but does not show up on DEXA bone density measurements. Estradiol and
progesterone supplementation reduce markers of bone turnover and increase bone density, adding
testosterone further increases bone density in the hip.265 Progesterone has a stimulatory effect on
bone formation.266 Progesterone supplementation alone helps build bone.267 It appears to either act
directly on bone by engaging an osteoblast receptor or indirectly through competition at a
glucocorticoid osteoblast receptor, reducing cortisol’s effect on bone.268 Adding testosterone
replacement to estradiol produces a greater increase in bone density than estradiol alone.269,270 DHEA
supplementation alone in older women increases bone density by 2 -4% in 2 years.271
Because doctors think that all menopausal hormone replacement is dangerous, (See Appendix) they
treat the bone loss caused by sex-steroid deficiencies with bisphosphonate drugs (Fosamax®, Boniva®,
Actonel® etc.) These compounds no only do not work as hormone replacement to increase
radioagraphic bone density,272,273 they produce abnormal bone that cannot respond properly to injury
and eventually becomes weak. These drugs are derived from soap molecules and have the effect of
poisoning the osteoclasts. The cessation of bone resorption temporarily increases radiographic bone
density and even bone strength, but at the cost of suppressing normal bone turnover. Because old bone
is no longer removed, new bone formation is eventually inhibited.274 The bone cannot adapt to stresses
or injury. Bisphosphonates are associated with osteonecrosis of the jaw (“rotting jaw”) in women after
tooth extractions and other dental surgery.275 The jaw cannot make new bone as needed to fill in the
void left by the tooth. Orthodontists have also noticed that appliances and braces cannot move the
teeth in women on a biphosphonate. Bisphosphonates also delay healing of fractures.276 Worst of all,
after 8 years or so, they produce weak bones that can fracture without any trauma—especially in the
femur.277,278 Biphosphonates have also been associated with a number of side effects including
gastrointestinal problems, muscle and joint pain, and eye inflammation.279 Evista® (raloxifene) is in a
class of non-bioidentical hormone-like drugs known as selective estrogen receptor modifiers, or
“designer estrogens”. These drugs do not relieve the other negative effects of menopause, do not have
the same health benefits as estradiol, and can have negative health consequences. The only proper
prevention and treatment for osteoporosis in women is hormone restoration, accompanied by sufficient
Vitamin D and Vitamins K1280,281 and K2282.
In summary, the evidence shows that;



Estradiol, testosterone, and progesterone deficiencies cause bone loss.
The proper treatment for osteopenia and osteoporosis is hormone replacement.
Bisphosphonates and designer estrogens should be avoided.
Sex Steroid Deficiency and Dementia
Estradiol receptors are found
Estrogen Replacement
Prevents Alzheimer’s Disease
throughout
the
brain,283
and
sufficient estradiol is necessray to
normal brain function.284 An almost
universal
symptom
of
estradiol
deficiency is brain dysfunction. It
appears as poor recall of familiar
Longer duration
information,
lower
mood,
and
insomnia. The memory degradation
72% used Premarin only
Zandi PP, et al., Cache County Study. JAMA. 2002 Nov 6;288(17):2123-9
RR 0.46 in Kawas C, The Baltimore Longitudinal Study of Aging. Neurology 1997;48:1517-1521
RR 0.65 Paganini-Hill A, Arch Intern Med 1996;156:2213-2217
RR 0.4, Tang M-X, Lancet 1996;348:429-432
is also a warning sign of early mental
deterioration leading to dementia.
Estradiol and progesterone protect
against neurotoxicity by various mechanisms.285,286 Testosterone and estradiol decrease -amyloid
secretion in neuronal cultures. Orchiectomized rats have tendency to hippocampal cell death that is
reversed with testosterone replacement.287 Oophorectomy increases a woman’s risk of dementia288 and
Parkinson’s disease;289 the early the ovaries are removed, the greater the risk.290 Bilateral oophorectomy
before age 45 increases mortality from neurological and mental disease by 5-fold.291 After the age of 80,
women suffer from much more dementia than men; they have a 4-fold greater risk by age 95. This risk
can be reduced by 50%, even elminated, by long-term estrogen therapy.292,293,294,295 Of course, the earlier
estradiol-progesterone-testosterone therapy is started, the greater the immediate and long-term
benefits. There will be little short-term benefit in women who have been severely estradiol-deficiency
for over 20 years. 296
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