Estrogens are naturally occurring steroidal hormones responsible for female reproductive system development and maintenance. They are of two basic characters chemically – steroidal and non-steroidal.

Steroidal estrogens

There are three major naturally occurring estrogens in women. These are:

• are estrone (E1)
• estradiol (E2)
• estriol (E3)

Of these Estradiol (E2) is the most common form found in nonpregnant females. Estradiol levels vary through the menstrual cycle, with levels highest just before ovulation. From menarche to menopause the primary estrogen is 17β-estradiol.

After the reproductive age, when a woman has achieved menopause, estrone or E1 becomes that primary estrogen. Estrone is weaker than estradiol. Similarly during pregnancy estriol is the primary estrogen. Estriol is considered a weak estrogen as well.

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. There is no definite scientific evidence to prove this hypothesis however.

Synthesis of steroidal estrogens

All three are produced from androgens through actions of enzymes. The primary molecule that begins the synthesis of estrogen is cholesterol. It forms androstenodione. Androstenedione is a substance of moderate androgenic activity. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted to estrone or estradiol, either immediately or through testosterone. This conversion of testosterone to estradiol, and of androstenedione to estrone, is catalyzed by the enzyme aromatase.

Prescribed estrogens compared to system estrogens

Oral estrogens are converted into estrone, with potential negative effects for the patient. This is not true for locally applied estrogen preparations like estrogen patch, creams, vaginal cream or estrogen given under the tongue. The cause for this is that oral estrogens are metabolized by the liver and exert different effects than systemic estrogens, which are not metabolized by the liver.
 

Another difference between oral and system estrogen is regarding growth hormone (GH). GH is an important hormone made by the pituitary that stimulates the liver to produce another hormone called IGF-1 or Insulin like Growth factor 1. IGF1 has several beneficial effects, including an increase in energy and sense of well-being. 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 thus can lead to high GH levels and also low IGF-1 levels. Both of these may have negative effects.

On the flip side, oral estrogens may be more effective than systemic estrogens in terms of improving some parameters related to heart disease. Oral estrogens are responsible for increase in good cholesterol, HDL. Oral estrogens may have other beneficial heart effects (anti-oxidant effects) compared to systemic estrogens.

The commonest prescribed estrogen is premarin. It contains conjugated equine estrogen (CEE). CEEs are harvested from the urine of pregnant mares and contain 3 to10 different estrogen components, many of which are converted to estrone. Due to its health risk, more genetic estrogen named Progynova (estradiol valerate) are now more often prescribed.

Non-steroidal estrogens

There are several synthetic and naturally occurring substances that possess estrogenic activity. Many of the synthetic derivatives are called xenoestrogens, plant estrogens are called phytoestrogens and estrogens from fungi are called mycoestrogens.

These are not always steroids. For example Equol, a phytoestrogen that is structurally similar to estradiol-17β. It was first found in the urine of mares and then in urine from goats, cows, sheep and hens. This phytoestrogen possesses weak estrogenic activity but also has antiestrogenic actions. It competes with estradiol-l7β to bind with the uterine cytosol receptors. It was subsequently shown to be the “contraceptive” agent responsible for an infertility syndrome (Clover disease) which was widespread in Australian agricultural animals.

Equol is not present in plants in significant quantities. However, plants contain formononetin, daidzein, and genistein. In animals, equol is formed in the gastrointestinal tract as the result of the bacterial degradation of these phytoestrogens which are ingested in large quantities in their feed.