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Question: You wrote about your concerns that androstenedione may be a health risk for some people by increasing estrogen levels. Do you have the same reservations about androstenediol? ——OTP

Answer: Any steroid precursor can get metabolized into estrogen (a collective term for estradiol, estrone and estriol). If you look at the many steroids in the steroid tree (see Figure 1 [below]), most lead to estrogens one way or another. The key enzyme in the production of estrogens is aromitase (the A-marked [blue] circles). If a line is drawn through the aromatase-catalyzed reactions, all of the estrogens are on one side of the line, and the anabolic and androgenic steroids are on the other side (see [red] dashed line). This means that aromitase is the gatekeeper that influences the relative dominance of estrogenic versus anabolic/androgenic influences within the steroidal hormonal system.

The two primary aromitase pathways are 1) the conversion of androstenedione to estrone, and 2) the conversion of testosterone to estradiol (the leftmost arrows crossing the dashed line). Since estradiol and estrone readily interconvert (note the bidirectional arrows), the particular pathway to estrogen is not very significant from the estrogen perspective (i.e., on the estrogen side of the line). There is, however, a major difference on the androgen/anabolic side of the line. Aromitase has ten times (!) higher affinity for androstenedione than testosterone. In the way of an analogy, the androstenedione-to-estrone pathway is a four-lane highway and the testosterone-to-estradiol pathway is a residential side street. I think this puts androstenedione at a distinct disadvantage compared to testosterone regarding potential estrogenic side effects.

This estrogenic disadvantage of androstenedione is not shared by androstenediol. If you follow the pathways, you see that androstenediol is not a direct substrate for aromitase and must first be 1) converted to testosterone, 2) converted to DHEA and then to androstenedione, or 3) converted to testosterone and then to androstenedione before it can be converted to estrogens by aromatase. Note that one of the key enzymes in these three alternatives is 17-beta-hydroxysteroid dehydrogenase, the same enzyme that interconverts estradiol and estrone. This same enzyme allows androstenediol and DHEA to interconvert, and testosterone and androstenedione to interconvert.

If you trace the pathways, you will see that there is estrogenic potential from all of the primary steroid precursors: DHEA, progesterone and pregnenolone. The degree of estrogenic influence depends on the specific activities of many enzymes, each of which may depend on sex, genetics, and a variety of individual metabolic idiosyncrasies. The estrogenic risk of DHEA depends on the the activity of 3-beta-hydroxysteroid dehydrogenase and delta-4,5-isomerase (the 3-marked circles). The estrogenic potential of progesterone depends primarily on 17-alpha-hydroxylase (the 2-marked circles). Pregnenolone’s potential estrogenic influence depends on both these enzyme systems.

The easiest way to find out how these enzyme systems work is to observe them in action. Measuring DHEA, progesterone, testosterone and estradiol before and after any supplementation with a steroid precursor allows us to observe the resulting shifts in hormone ratios that allows us to infer enzyme activities. This is why before-and-after testing is essential for steroid hormone replacement therapy. ——SWF