By John R. Lee, MD

As should be clear by now, progesterone and estrogen are closely interrelated in many ways.  Progesterone is a precursor in the normal biosynthetic pathway for estrogen.  They are often antagonistic, and each sensitizes receptors for the other.  Our understanding of progesterone will be enhanced if we understand estrogen a bit better as well.

First, there is a semantic problem to clear up.  Early researchers found evidence of an estrus-producing hormone (i.e., estrogen) and then, in 1929, Comer and Allen established the existence of a corpus luteum hormone necessary for the successful promotion of gestation (i.e., progesterone).

Then, estrogen was found to be not one hormone but a group of similar hormones of varying degrees of activity, all made by the ovary.  Each, as they were found, was given a specific chemical name and the word “estrogen” became the name of the class of hormones with estrus activity.

The three most important hormones of this estrogen class are estrone, estradiol, and estriol.  In popular writing, however, each of the specific members of the class continues to be referred to as estrogen.

In the case of progesterone, only a single hormone is found.  Thus, “progesterone” is both the name of the class and of the single member of the class.

This confusion still exists in the minds of many physicians and writers.  Gail Sheehy, in her popular 1991 book The Silent Passage, admits to being so confused about the names that she decided to call all of them “progesterone” in the book, even though she is generally writing about the synthetic progestins.1

Later, when plant extractions were found to have progestational activity and, even later, when synthetic versions with progestational activity were created, various authors described them as “progestins,” or “gestogens,” or “progestagens.”  Unfortunately, in the pharmaceutical promotion that followed, the word “progesterone” was also used to describe these other compounds with the ability to sustain the human secretary endometrium, despite their many side effects (not found in progesterone) and the lack of many of the other abilities of natural progesterone as produced by the corpus luteum.

The word “estrogen” generally refers to the class of hormones produced by the body with somewhat similar estrus-like actions.  Phytoestrogens refer to plant compounds with estrogen-like activity, and xenoestrogens refer to other environmental compounds (usually petrochemical) with estrogen-like activity.

The compound p-Anol is an active estrogenic agent found in fennel and anise.  Diethylstilbestrol (DES), which resembles two molecules of p-Anol linked end to end, is fully as potent as the most active gonadal hormone, estradiol.  It can be inexpensively synthesized and is highly active when taken orally.  In the past it was used for regulation of the menstrual cycle, in contraceptives, and to prevent premature labor.  However, it has been implicated in certain types of cancer (e.g., cervical cancer in daughters of mothers who were given DES during pregnancy), and its use has been superseded by other presumably less dangerous compounds.  DES was also used most extensively in beef cattle to fatten them up more quickly for slaughter.  Studies have shown that exposure to estrogenic compounds is probably a significant causal factor in the increased incidence of breast cancer and the steep decline in male sperm production.

A common feature of estrogenic compounds is the phenolated A-ring of the molecule.  This molecular configuration of a phenolated A-ring, as in estrogens, is not present among progesterone, testosterone, and corticosterone molecules.  Most likely, this difference is the reason for estrogen’s different receptor specificity and physiologic actions.

Phenolic compounds are common among petrochemical derivatives which are pervasively polluting our environment.  Some of these are extremely potent estrogenic compounds (called xenoestrogens), even at nanogram doses.  Known xenoestrogens include plant-produced coumetrol, equol, tetrahydrocannabinol, zearalenone;  pesticides such as DDT and kepone;  and a combustion by-product, 3,9-D-dihydroxybenz anthracene.2

This unrecognized exposure to estrogenic compounds is probably a significant causal factor in the breast cancer and the recently identified steep decline in male sperm production.

Estrogen Synthesis

Because of their respective position in the biosynthetic pathway, estrone is referred to as El, estradiol as E2, and estriol as E3.  In the non-pregnancy state, E1 and E2 are produced by the ovary in microgram quantities, and E3 is only a scant byproduct of E1 metabolism.  Relative serum E1 and E2 levels are determined less by their synthesis rate than by a reversible liver redox system, which can convert one into the other and results in higher levels of E2.

During pregnancy, however, the placenta is the major source of estrogens;  E3 is produced in milligram quantities, while E1 and E2 are produced in microgram amounts.  E2 excretion now becomes least.  Instead of de novo synthesis from acetate via cholesterol, pregnenalone, or progesterone, placental E3 synthesis requires DHEA obtained from DHEA-S (sulfated DHEA) of either maternal or fetal (adrenal) origin.

Because of fetal participation in E3 formation, serum E3 measurements can be a sensitive clinical indicator of placenta and/or fetal status.  The placenta also becomes the major source of progesterone, producing 300-400 milligrams per day during the third trimester.  The placenta also becomes the major source of progesterone, producing 300-400 milligrams per day during the third trimester.  Estriol (E3) and progesterone, therefore, are the major sex steroids during pregnancy.

Both estriol and progesterone are essentially devoid of the ability to affect secondary sex characteristics, and thus the sexual development of the fetus is determined solely by its own DNA and not the sex hormones of the mother.  Lurking as an unknown factor in the later development of one’s sexual preference is the possibility of influence by the xenoestrogens of our petrochemically-polluted environment.  Since this factor of slow metabolism and excretion is true of all synthetic estrogens, in all cases of estrogen supplementation, the natural hormones would be superior.

Among the three estrogens, estradiol is most stimulating to the breast, and estriol is the least, their relative ratio of activity being 1000: 1.  Studies two decades ago found estradiol (and estrone to a lesser extent) to increase one’s risk of breast cancer whereas estriol is protective.

Synthetic ethinylestradiol, commonly used in estrogen supplements and contraceptives, is even more of a risk because of high oral absorption and slow metabolism and excretion.  Since this factor of slow metabolism and excretion is true of all synthetic estrogens, one would think that, in all cases of estrogen supplementation, the natural hormones would be superior.

Conversely, estriol is the estrogen most active on the vagina, cervix and vulva.  In cases of postmenopausal vaginal dryness and atrophy which predisposes a woman to vaginitis and cystitis, estriol supplementation would theoretically be the most effective (and safest) estrogen to use.

Estrogen Effects

Estrogen might be thought of in terms of procreation and survival of the fetus.  It would seem advantageous to the baby for the expectant mother to be able, in times of famine, to store body fat.  Thus, the effects of estrogen include far more than merely its action on creating the female body form and its stimulation of the uterus and breasts.  During times of consistent dietary abundance, estrogen’s effects are potentially deleterious.  It is worthwhile to compare the physiological effects of estrogen and progesterone.

Estrogen effects:  Progesterone effects:

• Creates proliferative endometrium

• Breast stimulation

• Increased body fat

• Salt and fluid retention

• Depression and headaches

• Interferes with thyroid hormone

• Increased blood clotting

• Decreases libido

• Impairs blood sugar control

• Loss of zinc and retention of copper

• Reduced oxygen levels in all cells

• Increased risk of endometrial cancer

• Increased risk of breast cancer

• Slightly restrains osteoclast function

• Reduces vascular tone

• Maintains secretory endometrium

• Protects against breast fibrocysts

• Helps use fat for energy

• Natural diuretic

• Natural anti-depressant

• Facilitates thyroid hormone action

• Normalizes blood clotting

• Restores libido

• Normalizes blood sugar levels

• Normalizes zinc and copper levels

• Restores proper cell oxygen levels

• Prevents endometrial cancer

• Helps prevent breast cancer

• Stimulates osteoblast bone building necessary for survival of embryo

• Precursor of corticosterone production

Estrogen Dominance (Unopposed Estrogen)

It is clear that many of estrogen’s undesirable side effects are effectively prevented by progesterone.  It has been proposed that a new syndrome be recognized:  that of estrogen dominance, whether it occurs as a result of erogenous estrogen given postmenopausally or during the premenopausal anovulatory phase so common these days.

Unfortunately, it is the custom of contemporary medicine to prescribe estrogen alone for women without intact uteri and, equally unfortunate, premenopausal estrogen dominance is simply ignored.

“The more important factor in osteoporosis is the lack of progesterone, which causes a decrease in osteoblast-mediated new bone formation.”  The most common reason offered for postmenopausal women to take estrogen is protection against osteoporosis.

Here the picture is quite clear:  a lack of estrogen stimulates the osteoclast bone cells to increase bone resorption.  However, this effect fades in five years or so and, thereafter, bone loss continues at the same pace as in those women not using estrogen.

The more important factor in osteoporosis is the lack of progesterone, which causes a decrease in osteoblast-mediated new bone formation.

Reprinted from the literature of Women’s International Pharmacy.