Androstenedione

Androstenedione (also known as 4-androstenedione) is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.

Synthesis


Androstenedione is the common precursor of male and female sex hormones. Some androstenedione is also secreted into the plasma, and may be converted in peripheral tissues to testosterone and estrogens.

Androstenedione can be synthesized in one of two ways. The primary pathway involves conversion of 17-hydroxypregnenolone to dehydroepiandrosterone by way of 17,20-lyase, with subsequent conversion of dehydroepiandrosterone to androstenedione via the enzyme 3-β-hydroxysteroid dehydrogenase. The secondary pathway involves conversion of 17-hydroxyprogesterone, most often a precursor to cortisol, to androstenedione directly by way of 17,20-lyase. Thus, 17,20-lyase is required for the synthesis of androstenedione, whether immediately or one step removed.

Androstenedione is further converted to either testosterone or estrogen. Conversion of androstenedione to testosterone requires the enzyme 17β-hydroxysteroid dehydrogenase, while conversion of androstenedione to estrogen (e.g. estrone and estradiol) requires the enzyme aromatase.

The production of adrenal androstenedione is governed by ACTH, whereas production of gonadal androstenedione is under control by gonadotropins. In premenopausal women, the adrenal glands and ovaries each produce about half of the total androstendione (about 3 mg/day). After menopause, androstenedione production is about halved, primarily due to the reduction of the steroid secreted by the ovary. Nevertheless, androstenedione is the principal steroid produced by the postmenopausal ovary.

Endocrine function
In females, androstenedione is released into the blood by theca cells. The function of this is to provide androstenedione substrate for estrogen production in granulosa cells, since these cells lack 17,20 lyase required for androstenedione. Similarly, theca cells lack the enzyme aromatase required to make estrogens themselves. Thus, theca cells and granulosa cells work together to form estrogen.

History
Androstenedione was manufactured as a dietary supplement, often called andro (or andros) for short. Sports Illustrated credits Patrick Arnold for introducing androstenedione to the North American market. Andro was legal and able to be purchased over the counter and consequently it was in common use in Major League Baseball throughout the 1990s by record-breaking sluggers like Mark McGwire. The supplement is banned by the World Anti-Doping Agency, and hence from the Olympic Games.

On March 12, 2004, the Anabolic Steroid Control Act of 2004 was introduced into the United States Senate. It amended the Controlled Substance Act to place both anabolic steroids and prohormones on a list of controlled substances, making possession of the banned substances a federal crime. The law took effect on January 20, 2005. Surprisingly, androstenedione was legally defined as an anabolic steroid, even though there is scant evidence that androstenedione itself is anabolic in nature.

On April 11, 2004, the United States Food and Drug Administration banned the sale of androstenedione, citing that the drug poses significant health risks commonly associated with steroids.

Androstenedione is currently banned by the U.S. military.

The Andro-Project
The "Andro-Project", conducted by medical researchers at East Tennessee State University, showed that the supplement "Andro"(androstenedione/androstenediol) does not increase muscle mass or strength.

Biological effects
Androstenedione has been shown to increase serum testosterone levels over an eight-hour period in men when taken as a single oral dose of 300 mg per day, but a 100 mg dose had no significant effect on serum testosterone. However, serum levels of estradiol increased following both the 100 mg and 300 mg doses. The study also reported that the serum level of estrogens and testosterone produced varied widely between individuals. A 2006 review paper summarized several studies which examined the effect of androstenedione on strength training. At dosages of 50 mg or 100 mg per day, andro had no effect on muscle strength or size, or on body fat levels. One study used a daily dosage of 300 mg of androstenedione combined with several other supplements, and also found no increase in strength when compared to a control group that did not take the supplements. The review authors speculate that sufficiently high doses may indeed lead to increased muscle size and strength. However, due to the federal ban on androstenedione supplements, it is difficult to carry out new research on its positive and negative effects. The review authors conclude that individuals should not use androstenedione supplements due to the lack of evidence of beneficial effects, the wide variation in individual responses to the supplement, and the risk of unknown side effects.

Because androstenedione is converted in part to estrogens, people taking this supplement may have estrogenic side effects, although none of the studies cited above used a sufficiently high dosage to draw any conclusions.