Understanding Competitive Inhibition
by Kevin Pezzi, MD

• Phytoestrogens are chemicals with estrogen activity that occur naturally in a variety of plants such as soybeans, some other beans, flaxseed oil, licorice, beer, bourbon, rye, cabbage, spinach, cashews, peanuts, dates, oats, corn, wheat, apples, almonds, carrots, garlic, fennel, anise, celery, and certain herbs. You may have heard that eating yams is effective as a means of estrogen replacement. This is not true. The "yams" sold in the United States are usually sweet potatoes, which do not have significant estrogen or progesterone activity. True yams contain diosgenin, which can be converted in a laboratory—but not your body—into progesterone. Yams are virtually inedible because of their soapy, bitter taste. American yams are edible, but do not contain diosgenin.
  
  On a milligram-for-milligram basis, phytoestrogens are much weaker than natural estrogens. However, phytoestrogens can still exert significant effects because they are sometimes consumed in large quantities, hundreds or thousands of times more than the endogenous production of estrogen. Furthermore, phytoestrogens can exert a powerful effect by blocking the effects of stronger hormones.
  
  Some phytoestrogens are produced in the intestine when bacteria normally resident there metabolize certain plant substances into compounds with estrogenic activity. Since oral antibiotics can suppress the normal bacterial flora in the intestines, antibiotics can indirectly affect estrogen activity.


• Xenoestrogens are man-made chemicals that mimic natural estrogens.


• Designer estrogens are drugs, such as tamoxifen or raloxiphene, given to women to achieve specific effects such as treating breast cancer or preventing osteoporosis.


• Exogenous estrogens are animal estrogens introduced into women either purposely (e.g., Premarin^®, intended as an estrogen supplement after menopause) or unintentionally, as from ingestion of food containing animal estrogens. Premarin^® is derived from the urine of pregnant mares and contains estrone (also a human estrogen) and equilin (a horse estrogen) and other estrogens in smaller amounts.

Not all women have designer estrogens, but virtually every woman and man has phytoestrogens, xenoestrogens, and exogenous estrogens in their bodies that interfere with the action of natural estrogen and testosterone. The interactions between this slew of estrogens is complex, occasionally producing beneficial results but oftentimes creating bothersome or even dangerous effects.

All of the estrogens achieve their effects by binding to receptors. You can think of the various estrogens (including phytoestrogens, xenoestrogens, designer estrogens, and exogenous estrogens) as being different keys, and the receptors as being different locks. When the correct key (estrogen) fits into a lock (receptor), it can open it up (trigger an estrogen response, such as softening of the skin). In reality, the various estrogens can have effects beyond just triggering or not triggering a response. An estrogen can bind to a receptor and trigger a full response, trigger a partial response, or simply just sit there and block other potentially more active estrogens from binding and achieving an effect. This is the crux of competitive inhibition.

Competitive inhibition is a process in which two or more different hormones compete for the same receptor, and post-receptor effects are proportionately reduced with increasing concentration of the molecule having a weaker receptor response. Stated another way, different molecules may attach to the same receptor, but they do not usually cause the same degree of response on the part of the receptor. Hormones, like estradiol, achieve their effects through receptor binding and activation. However, if some other substance with weak estrogen activity is able to bind to the receptor it limits the ability of estradiol itself to bind. In the absence of estradiol or another similar "strong" estrogen, any receptor binding by molecules with weak estrogen activity will induce a weak estrogen response. However, if a strong estrogen is present (such as in a premenopausal woman, or a postmenopausal woman on estrogen replacement therapy [ERT]), receptor binding by weak estrogens simply limits the ability of the stronger estrogen to bind to estrogen receptors (since both molecules cannot occupy the same receptor at the same time), thus blunting the ultimate estrogen effect.

Another way to conceptualize the competitive inhibition of estrogens is to think of a strong estrogen (such as estradiol) as being black paint, a weak estrogen (such as a phytoestrogen) as being gray paint, and a severe estrogen-deficient state as being white paint. If gray paint is added to white paint, it will make the white paint more gray. However, if gray paint is added to black paint, it will make it whiter.

After menopause, the natural production of estrogen plummets. Postmenopausal women sometimes supplement their diets with soybean products as a source of phytoestrogens to reduce their hot flashes and other undesirable symptoms. Competitive inhibition explains why phytoestrogens (which are comparatively weak estrogens) may increase the overall estrogen effect in postmenopausal women not on ERT, yet reduce the estrogen effect in premenopausal women or postmenopausal women on ERT.

Most people—including many doctors—fail to consider how the various estrogens interact with the different estrogen receptors present in the various estrogen-responsive tissues of the body, such as the breast, uterus, and vagina. While these interactions are complex, they can be boiled down to one thing: are the effects additive, or does competitive inhibition occur?

Let’s consider a simple example in which a woman has a moderate amount of estradiol. If she were given more estradiol, her overall estrogen effect would increase; this is an example of an additive effect. On the other hand, if she were given estriol (a comparatively weak estrogen), her overall estrogen effect would decrease because estriol would compete with estradiol for space on receptors and hence exert a competitive inhibition effect.

While this simplification is generally true, it must be qualified by considering two more facts that are, fortunately, also easy to understand:

• The strength of a given estrogen is dependent upon not just the properties of the estrogen but also of the receptors in the target tissue. For example, while estriol is comparatively weak its effect upon the vagina is much stronger than its effect upon the breast. This concept is crucial and can be exploited to achieve very beneficial effects. For instance, if a postmenopausal woman wished to reduce her risk of breast cancer but also prevent vaginal atrophy and dryness, she could use estriol.

• Competitive inhibition can be effectively overturned if the concentration of the weaker estrogen is sufficiently great. Let’s again consider the example of a woman who has a moderate amount of estradiol. If she were given a somewhat weaker estrogen, the weaker estrogen could block the effects of the estradiol to some extent by competitive inhibition and thus reduce the net estrogen effect. However, if the concentration of the weaker estrogen is very high, it will still partially block the effects of estradiol but yet stimulate the receptors so much that the overall estrogen effect increases.