Chemical Structure of Estrogen

Estradiol is only one member of the estrogen family.

The word "estrogen" comes from Latin roots that mean, literally speaking, anything that brings a female animal into heat--i.e., a promoter of estrus or readiness to mate. Scientifically, the word refers to a family of molecules involved in regulating the female reproductive cycle. The three estrogens in women include estradiol (which is the molecule most commonly called "estrogen"), estrone and estriol. Other, functionally similar molecules found not in humans but in animals and even plants are referred to as estrogens as well.

Thus, no single chemical structure represents "estrogen." And since structure plays a key role in function, estrogen-like chemicals do not all act in the same way.

Estrogens Are Steroids

Testosterone, like the estrogens, is a steroid. Small changes make a big difference!

The three human estrogens share strong family resemblance, but they are not the same molecule. In fact, all steroids (including not only estrogens but the functionally very different male hormone, testosterone) derive from cholesterol.

The human estrogens share certain structural characteristics reminiscent of their origin: three six-membered rings and one five-membered ring that share sides. The difference is in the details, and these details make all the difference in the molecule's functionality.

Comparing Human Estrogens

Estriol is the weakest of the three human estrogens.

Human estradiol is the "strongest" of the estrogens. That is, estradiol is the best at "ordering" cells to produce the many other proteins necessary for the normal reproductive cycle in a nonpregnant female. Estradiol is also present at the highest concentration in premenopausal women.

Although the structural differences between the estrogens are very subtle (less than a water molecule's difference between the three!), the next strongest estrogen, estrone, is 10 times weaker than estradiol.
The third, estriol, in turn is almost 10 times weaker than estrone.

Because the ovaries product most of the body's estrogens, and the ovaries cease to function at menopause, doctors and scientists have targeted estrogen hormone replacement therapy for reduction of menopausal symptoms such as hot flashes, vaginal dryness and night sweats.

Conjugated Equine Estrogens

Estrone is a major component of CEE.

For much of the 20th century, estrogens for hormone replacement therapy were derived from the urine of pregnant mares, which is rich in estrogen components. The structure and ratio of the estrogens in horse urine varies somewhat from those found in humans: Conjugated equine estrogens (CEEs), the active ingredient in many FDA-approved therapies, consists of 45 percent estrone and 25 percent equiline, an estrogen not produced in humans. Less than 10 percent of the formulation is estradiol, and there are several dozen other components.

Although many women have experienced great relief from their menopausal symptoms using formulations containing CEEs, the introduction of these nonendogenous estrogens can contribute to unwanted side effects and differences in how the molecules are eliminated from the body.

Synthetic Estradiol

Other estrogen replacement therapies contain synthetic estradiol, which is a pure form of the estradiol estrogen prepared from a natural precursor, diosgenin, found in soybeans and wild yams. This estrogen is structurally identical to human estradiol.

Although many non-FDA-approved preparations, in the wake of the HRT safety controversy in 2002, tout their use of "natural" or "bioidentical" estrogen, these preparations use the same synthetic estradiol found in many FDA-approved products.

Estradiol (from any source) converts to estrone in the liver, which makes it likely to have some of the same effects as estrone-rich CEE. When absorbed through the skin (using a transdermal patch or gel) estradiol does maintain its original structure initially in the bloodstream.

Other Estrogens

HRT and breast cancer treatments employ other estrogens and "anti-estrogens" with similar structures and functions. Because of the complexity of estrogen biochemistry, the pharmacology of different formulations is still under study and, in some cases, the subject of controversy.

References

• Harvard Health Publications: What are bioidentical hormones?
• Clinical Opinion: The Biologic and Pharmacologic Principles of Estrogen Therapy for Symptomatic Menopause
• Google Books: "Menopause for Dummies," excerpts from Chapter 11, The Basics of Hormone Therapy
• Google Books: "Principles of Medicinal Chemistry"; search results for "estrogen estradiol"
• Google Books: "Cancer chemotherapy and biotherapy: principles and practice"; search results for "estrogen structure"

Resources

• Clinical Opinion: The Biologic and Pharmacologic Principles of Estrogen Therapy
• What are bioidentical hormones?
• Menopause for Dummies