Natural Estrogens, Selective Estrogens, Fantasy Estrogens...What is the Perfect Estrogen?

Reprinted with the kind permission from Andrew Dott, MD, MPH and the Institute of Endocrinology and Reproductive Medicine

To understand the issue of alternative estrogen therapy, you need to understand where and how estrogen works in the body. Estrogen receptors (places where estrogen can bind to tissue and makes tissues do certain things) are found throughout the body. These include the uterus, breasts, vagina, skin, liver, brain, bone, blood proteins, and blood vessel linings. Although the thrust of estrogen replacement therapy during the last 50 years has been to alleviate the symptoms (e.g. hot flashes), as the goals of therapy have changed to long term health maintenance, it has become necessary to rethink what constitutes the ideal estrogen. For menopause replacement, one would ideally want a form of estrogen which has a positive effect on certain tissues, and a negative effect on others. Other goals are being able to avoid the use of a second drug to counteract the harmful effects of the first one (such as the use of progesterone, Provera) to counteract the uterine cancer risk from unopposed estrogen. Table I summarizes the effects of estrogen on various tissue receptors.

Table I: Effects of Estrogen at Various Sites in the Body
Tissue	Effect of Estrogen Receptor Stimulation	Clinical Effect of Stimulation	Clinical Effect of Absence of Stimulation
Bone	increased deposits of calcium into bone	increased bone density	osteoporosis
Brain	Blocks the release of ovarian estrogen	none	hot flashes, sleep disorders, mood changes, problems with memory??, Alzheimer’s disease??
Breast	Stimulates growth of breast tissue	Bigger breasts, ? increased risk of breast cancer, increased sensitivity of the breast,	Smaller breasts
Clotting of Blood	-	increased risk of blood clots	no change in clotting
*Blood Fats (Lipids) (increased LDL Cholesterol is bad) increased HDL Cholesterol is good**	-	increased HDL, decreased LDL, decreased Cholesterol,	decreased HDL, increased LDL, increased Cholesterol
Skin	increased fat deposits in skin	softer skin	thinner skin, liver spots, dry skin
Uterus	increased stimulation of uterine lining and muscle	heavier cycles, increased risk of uterine cancer	no periods
Vagina	increased thickening of skin, better blood supply to tissue	vaginal discharge, feelings of pelvic congestion	dryness, vaginal infections, painful sex, incontinence of urine, pelvic weakness

Obviously, the ideal estrogen should not cause any medical problems. Table II outlines the ideal estrogen for post menopausal estrogen replacement. This is somewhat different than natural estrogen (estradiol) which is produced by the human ovary or estriol, which is produced by the placenta, or estrone, which is produced by fatty tissue.

Certain plants, particularly soy and wild yams, contain isoflavones (phytoestrogens) which have estrogen like effects if consumed in large amounts. (One suggestion has been to consume approximately 1 pound of tofu / day to obtain sufficient soy protein (50gms)!!). The soy compounds are called genistein, daidzein, and glycitein. In fact, the estrogen-like compounds found in soy, red clover, and yams serve as the base for the synthesis by the pharmaceutical industry of virtually all estrogen and progesterone-like compounds used in clinical medicine. The only exception is Premarin which is derived from the urine of pregnant horses.

Many of these naturally occurring compounds have selective estrogen-like effects on tissues. These are called SERMs or Selective Estrogen Receptor Modulators. There are also synthetic compounds both now in use in clinical medicine and about to be commercially released which also have selective effects. An example is Tamoxifen which is an estrogen-like compound used in the treatment of breast cancer. It is an anti-estrogen on the breast and a pro-estrogen on the uterus, bone, and lipids. It does not relieve hot flashes.

A new drug which has just been released is raloxifene (Evista). This compound offers the advantage of negative stimulation on the breast and uterus and a positive stimulation on the bone and lipids. Women who do have a uterus will not have to use progesterone-like compounds to protect from uterine cancer. This avoids the side effects of progestins which can include depression, bloating, irritability, and pre-menstrual like symptoms. Evista, unfortunately, will not help with hot flashes (it may make them worse) so its use will probably be inappropriate for women in acute menopause. However, for the older woman who is not experiencing hot flashes, it may play an important clinical role.

Hopefully, one day the perfect estrogen will either be found as a naturally occurring compound or be synthesized by a pharmacological manufacturer.

Table II: Effects of Various Natural, Synthetic, Selective, and Phyto Estrogens in Human Tissue
	Uterine Lining	Breast	Skin	Vagina	Brain	Bone	blood clots	LDL Cholesterol HDL Cholesterol
Ideal Estrogen	neg	neg	pos	pos	pos	pos	neutral	pos pos
Estradiol	pos	pos	pos	pos	pos	pos	pos	pos
Premarin	pos	pos	pos	pos	pos	pos	pos	pos neutral
Tamoxifen	pos	neg	neutral	neutral	neg	pos	?	pos
Raloxifene	neg	neg	?	neg	? neg	pos	?	pos neutral
Black Cohosh	neutral	none	none	none	pos??	none	none	none
Genistein (Soy)	neg	neg		neutral	pos	pos		pos pos

courtesy of OBGYN.net