Dr. Friedman’s Guide to Estrogen Replacement
There are risks and benefits with all medicines and estrogen replacement is no
exception. In fact, estrogen replacement is one of the most controversial topics in
Endocrinology. This is due to conflicting data on its benefits and side effects, the
multitude of available hormone replacement products and regimens and the fact that most
studies on estrogen replacement have been performed using the heavily-marketed
estrogen preparation, Premarin. Because of its complexity, the decision about whether
you should be on estrogen replacement, and equally as important, what type of estrogen
replacement is correct for you, needs to be carefully thought out by you and your doctor.
Another controversial issue related to estrogen replacement is progesterone replacement.
Some information on estrogen/progesterone replacement and the benefits and side effects
of some of the available compounds are described below. Patients interested in
testosterone replacement are encouraged to read the article available on this website
entitled “Testosterone Replacement in Women”.
There are both definite and possible benefits and risks of estrogens. The definite
benefits include 1) improvement of menopause symptoms, such as hot flashes, night
sweats, vaginal dryness, insomnia, mood swings and depression and 2) increase in bone
density leading to prevention of osteoporosis. Possible benefits of estrogens include a
decreased likelihood of developing cardiovascular disease, improvement in lipids
(cholesterol), decreased risk of colon and rectal cancer and a prevention of memory loss
and cognitive decline. The definite risks of estrogens are endometrial cancer (reduced if
progesterone is given along with estrogen) and blood clots. Possible risks include an
increase in breast cancer and gallbladder disease. A recent study (the HERS study) found
that estrogen actually caused women who already have heart disease to have more heart
problems in the first year of taking estrogen, than women who were not given estrogen.
In the additional years of the study, both groups of women had similar incidence of heart
problems. It is important to emphasize that this was just one study and only evaluated
Estrogens also have side effects. These include worsening of estrogen-dependent
diseases, such as uterine fibroids and endometriosis. Other side effects include breast
tenderness and breast enlargement, vaginal bleeding, high blood pressure, nausea,
vomiting, headaches, jaundice and fluid retention (edema). In general, the higher the
dose, the more benefits and the more side effects are likely to occur.
Premenopausal women produce 3 biologically active estrogens, estrone (E1),
estradiol (E2) and estriol (E3). Estradiol is the most abundant estrogen produced and both
estrone and estradiol are potent estrogens. Estriol is considered a weak estrogen.
Although little scientific data supports the claim, it has been postulated that estrone is a
“bad” estrogen and may be the cause of estrogen’s cancer-causing properties, while
estriol is a “good” estrogen and may protect against cancer. Estradiol is probably neutral.
Oral estrogens, but not estrogens given by systemic routes (patch, skin cream, vaginal
cream, under the tongue), are converted into estrone, with potential negative effects for
the patient. Oral estrogens, because they are metabolized by the liver, likely exert
different effects than systemic estrogens, which are not metabolized by the liver.
The most commonly prescribed estrogen is Premarin, which is a conjugated
equine estrogen (CEE). CEEs are harvested from the urine of pregnant mares and contain
10 different estrogen components, many of which are converted to estrone.
Another recently recognized difference between oral and systemic estrogens has
to do with growth hormone (GH). GH is an important hormone made by the pituitary that
stimulates the liver to produce another hormone called IGF-1. GH, via IGF-1, has many
beneficial effects, including an increase in energy and sense of well-being. GH, itself, has
some negative effects including inducing diabetes. It has recently been found that oral,
but not systemic estrogen, blocks the effects of GH on stimulating IGF-1 at the liver.
Oral estrogens lead to high GH levels and also low IGF-1 levels, both with potential
negative effects. This is a theoretical reason to take systemic estrogens over oral
estrogens. On the other hand, oral estrogens may be more effective than systemic
estrogens in terms of improving some parameters related to heart disease. Oral estrogens,
but not systemic estrogens, increase the good cholesterol, HDL. Oral estrogens may have
other beneficial heart effects (anti-oxidant effects) compared to systemic estrogens.
Progesterone is usually given along with estrogen, because estrogen alone
(unopposed estrogen) is associated with endometrial hyperplasia and cancer.
Progesterone compounds substantially decrease this risk and are usually given along with
estrogen to women with an intact uterus. What is less appreciated is that progesterone-
containing compounds have their own side effects and benefits. Some of the side effects
include increased blood clots, rash, breast tenderness, weight gain, fatigue and
somnolence, edema and nausea. Some of the possible (largely unproven) benefits
(besides the reduction in endometrial hyperplasia and cancer due to unopposed estrogens)
include prevention of osteoporosis, improved mood and better sense of well-being.
Similar to the issue of estrogens, there are both natural and synthetic progesterones.
Synthetic progesterones are called Progestins and the most widely prescribed Progestin is
Provera. Recently, progesterone itself has become available as a drug called Prometrium.
It is postulated, but not proven, that natural progesterone is better for the patient than
The tables below of different readily available estrogen and progesterone containing
compounds may be helpful. These tables are not a complete list of all available
preparations, but are a guide to commonly available hormone preparations. Again I
recommend that your decision on whether to start hormone replacement and if so, what
type of hormone replacement, be carefully considered and arrived at in conjunction with
Estrogen compounds (available in US) for Hormone Replacement Therapy
E1-estrone, E2-estradiol, E3-estriol, CEE-conjugated equine estrogens
Progesterone compounds (available in US) for Hormone Replacement Therapy Progesterone/Estrogen Combination compounds (available in US) for Hormone Replacement Therapy
progesterones separatelyConvenient, probable best
adjust estrogens/progesterones separatelyNot recommended for
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