Androstenedione

In by Raphikammer

INTRODUCTION

Androstenedione (chemical name: 4-androstene-3,17-

dione) is a steroid hormone produced primarily in the reproductive

system and adrenal glands in men and women.

It circulates in the bloodstream and is the immediate precursor

to the potent anabolic/androgenic hormone testosterone

in the steroid synthesis pathway. Despite this well known

physiological classification, as well as a growing

body of evidence demonstrating that orally administered

androstenedione is converted to more potent steroid hormones,

the United States Food and Drug Administration

originally classified the hormone as a “dietary supplement.”

As such, it was available to the general public

without a prescription and for nearly a decade could be

easily purchased in health clubs, nutrition stores, and

over the Internet. This over-the-counter availability of

androstenedione came to an end when Food and Drug

Administration banned its sale in early 2004. The ban

was then codified with the passing of the 2004 Anabolic

Steroid Control Act. This law reclassified androstenedione

as an anabolic steroid and hence a controlled

substance.

GENERAL DESCRIPTION

The original and seemingly contradictory classification of

androstenedione as a dietary supplement was based on

the definition set forth in the 1994 Dietary Supplement

Health and Education Act (DSHEA). According to the

DSHEA, a substance was defined as a dietary supplement

if it was a “product (other than tobacco) intended

to supplement the diet that bears or contains one or more

of the following dietary ingredients: a vitamin, mineral,

amino acid, herb or other botanical. . . or a concentrate,

metabolite, constituent, extract, or combination of any ingredient

described above.” Hence, because androstenedione

could be synthesized from plant products, it fell

under that umbrella. Furthermore, the DSHEA specified

that the Department of Justice could not bring action to

remove a product unless it was proven to pose “a significant

or unreasonable risk of illness or injury” when

used as directed. Not surprisingly, after the passing of the

DSHEA, the use of dietary supplements increased dramatically.

In fact, by 1999, the dietary supplement industry

in the United States was generating annual sales of $12

billion (1).

Initially, androstenedione use was primarily confined

to athletes in strength and endurance-related sports,

an interest that seems to have sprung from reports of

its use in the official East German Olympic athlete doping

program. The event that most dramatically sparked

widespread curiosity in androstenedione, however, was

the media report that the St. Louis Cardinals baseball

player Mark McGwire had used androstenedione in the

1999 season (during which he broke the record for most

home runs in a season). The publicity that surrounded

this supplement also prompted an increased interest in

related “prohormones,” such as norandrostenedione and

androstenediol. This then led to a proliferation of claims

concerning the potential benefits of androstenedione use.

Manufacturers credited these products not only with

promoting muscle growth and improving athletic performance

but also with increasing energy, libido, sexual

performance, and general quality of life. Additionally,

androstenedione was often packaged in combination

with other substances as part of an intensive nutritional

approach to performance enhancement. An example

of such a combination is shown in Figure 1.

Clearly, the use of androstenedione and related compounds

during that time went well beyond the accumulation

of data that could provide a rational basis for

their use.

PROHORMONE FACTORS

  • 4-Androstenedione: 100 mg
  • 19-Nor-5-Androstenedione: 50 mg
  • 5-Androstenediol: 50 mg
  • DHEA: 50 mg
  • GH/1GF FACTORS
  • L-Arginine Pyroglutamate: 2500 mg
  • L-Ornithine Alpha-Ketoglutarate: 1250 mg
  • Taurine: 750 mg
  • Colostrum: 250 mg
  • LH BOOSTER
  • Tribulus: 250 mg
  • Acetyl-L-Carnitine: 250 mg
  • L-Carnitine: 100 mg
  • DHT BLOCKERS
  • Saw Palmetto: 200 mg
  • Beta Sitosterol: 200 mg
  • Pygeum Africanum: 50 mg

ESTROGEN BLOCKERS

  • Kudzu: 100 mg
  • Chrysin: 250 mg
  • 4-Androstenedione
  • Dehydroepiandrosterone
  • Estrone
  • HCOOH
  • HCOOH
  • 17β-HSD
  • CYP19 (aromatase)
  • CYP19 (aromatase)
  • 17β-HSD
  • 3β-HSD
  • Testosterone Estradiol-17β

BIOCHEMISTRY AND PHYSIOLOGY

Androstenedione is a steroid hormone that is produced

primarily in the adrenals, testes, and ovaries. It is classified

as a “weak androgen” because it binds to the body’s

receptor for androgen hormones in a much less potent

fashion than classic anabolic/androgenic steroids such

as testosterone (2). It is synthesized from the precursor

hormone dehydroepiandrosterone (itself a dietary supplement)

and is the direct precursor to testosterone. In normal

physiological circumstances, androstenedione can also be

converted to potent feminizing hormones such as estrone

and estradiol (both members of the “estrogen” class of hormones).

The relationship between androstenedione, other

steroid hormones, and the enzymes involved in the conversion

of androstenedione to testosterone and estrogens

is shown in Figure 2.

Importantly, the enzymes that convert androstenedione

to potent hormones such as testosterone and estradiol

are active not only in endocrine glands but also in

many peripheral body tissues such as muscle, bone, liver,

and brain (3). Thus, if orally administered androstenedione

has biological activity, it may act either directly or

by conversion to these more potent agents.

ANDROSTENEDIONE USE

There were no precise data concerning the prevalence of

androstenedione use in the general population during the

time that it was widely available. Our best estimates were

based on industry sales figures and extrapolations from

data on classic anabolic/androgenic steroid use in specific

populations. For example, in 1997, it was estimated that

4.9% of male and 2.4% of female adolescents in the United

States had used illegal anabolic steroids (4). Because these

substances were so readily available, there was concern

that androstenedione use in this particularly susceptible

population may have greatly exceeded these numbers.

In fact, in a survey administered in five health clubs in

Boston, Massachusetts, in 2001, 18% of men and 3% of

women respondents admitted to using androstenedione

or other adrenal hormone dietary supplements at least

once. These percentages suggested that as many as 1.5

million U.S. health club members alone may have used

these substances (5).

PHARMACOKINETICS AND HORMONAL EFFECTS OF

ANDROSTENEDIONE IN MEN

Because so many of the claims that surrounded androstenedione

were based on the premise that oral administration

increases serum testosterone levels, it may

be surprising to some that prior to 1999, there was only a

single published study investigating the ability of orally

administered androstenedione to be converted to more

potent steroid hormones (6). In this study, two women

were given a single dose of androstenedione, and the

levels were subsequently measured over the next several

hours. Since 1999, however, numerous small studies

(mostly in men) have investigated the effects of the supplement

(6–16). In general, these studies report that serum

androstenedione levels increase dramatically after oral administration

and thus confirm that a significant portion of

the supplement is absorbed through the gastrointestinal

tract after ingestion. However, the answer to the more important

question, namely, whether it is then converted to

more potent steroid hormones such as testosterone and

estradiol, appears to be complex. In general, these studies

suggest that the ability of oral androstenedione to increase

estrogen and testosterone levels in men is dose dependent

and is possibly related to the age of the study population

as well. Specifically, the bulk of the research indicates that

when androstenedione is administered to men in individual

doses between 50 and 200 mg, serum estrogen levels

increase dramatically. However, larger individual doses

(e.g., 300 mg) are required to increase serum testosterone

levels.

For example, King and colleagues studied the effects

of a single 100-mg oral dose of androstenedione in 10 men

between the ages of 19 and 29 and reported that although

serum androstenedione and estradiol levels increased significantly,

testosterone levels did not change (13). These

investigators then specifically measured the portion of circulating

testosterone that is not bound to protein and considered

the “bioactive” portion (called “free testosterone”)

and similarly saw no effect of the supplement. In a separate

study, Leder and colleagues gave 0, 100, or 300 mg

of androstenedione to normal healthy men between the

ages of 20 and 40 for seven days and took frequent blood

samples on days 1 and 7 (14). As in the study by King, they

also found that men receiving both the 100- and 300-mg

doses of androstenedione experienced dramatic increases

in serum estradiol that were often well above the normal

male range.

Percentage change in serum testosterone and estradiol in healthy

men after a single androstenedione dose (as measured by eight hours of

frequent blood sampling). Source: Adapted from Ref. 14.

did not affect serum testosterone levels. As shown in

Figure 3, however, the novel finding of this study was

that 300 mg of androstenedione increased serum testosterone

levels significantly, even though by only a modest

amount (34%).

Leder and colleagues further observed that there

was a significant degree of variability among men with

regard to their serum testosterone response after androstenedione

ingestion. As shown in Figure 4, some subjects,

even in the 300-mg dose group, experienced relatively

little change in testosterone levels, whereas serum

testosterone levels doubled in other men. This finding

suggests that there may be individual differences in the

way androstenedione is metabolized that could impact

any one person’s physiological response to taking the

supplement.

Brown and colleagues investigated the hormonal response

in a group of men between the ages of 30 and

Figure 4 Individual variability in the peak serum testosterone level

achieved after a single 300-mg dose of androstenedione in men. Each line

represents one study subject. Source: Adapted from Ref. 14.

56 (10). In this study, subjects consuming 100 mg of androstenedione

three times daily experienced increases in

serum estrogens but not in serum testosterone. However,

unlike in the study by King and colleagues discussed in the

previous text, free testosterone did increase significantly

(even though again by only a small amount).

Finally, several studies have compared the hormonal

effects of androstenedione with those of other

“prohormone” dietary supplements. Broeder and colleagues

studied the results of a 100-mg twice-daily dose

of oral androstenedione, androstenediol (a closely related

steroid hormone), or placebo in men between

the ages of 35 and 65 (7). They found that both compounds

increased estrogen levels but neither affected total

serum testosterone levels. Similarly, Wallace and colleagues

studied the effects of 50-mg twice-daily doses

of androstenedione and DHEA in normal men and reported

no increases in serum testosterone levels with

either (16).

EFFECTS ON MUSCLE SIZE AND STRENGTH IN MEN

The results of the studies discussed earlier suggest that

androstenedione use in men would be less likely to promote

the muscle building and performance-enhancing

effects associated with testosterone use and more likely

to induce the undesirable feminizing effects associated

with estrogens. Several studies have assessed the ability

of androstenedione (with or without exercise) to increase

muscle size and strength and have been uniformly

disappointing (7,9,13,15,16). For example, Broeder

and colleagues, in the study described earlier, also

measured changes in body composition and strength

in subjects taking 100 mg androstenedione twice daily

in combination with a 12-week intensive weight-training

program (7). Despite using sensitive methods that can detect

small changes in body composition, they found no

differences in muscle mass, fat mass, or strength in the

subjects receiving androstenedione compared with those

receiving a placebo tablet. Importantly, however, in this

study as well as all of these studies referenced earlier,

the supplement was given in doses that were not sufficient

to increase testosterone levels. It thus remains unknown

whether doses of androstenedione sufficient to increase

testosterone levels enhance muscle mass or athletic

performance.

METABOLISM OF ANDROSTENEDIONE IN MEN

One of the consistent findings of the various androstenedione

studies in men is the inefficiency of conversion of

the supplements to testosterone. Leder and colleagues explored

this issue further by investigating the pattern of

androstenedione metabolism in healthy men (17). Specifically,

they measured the concentration of inactive testosterone

metabolites (also called “conjugates”) in the urine

of subjects ingesting androstenedione and found an increase

of over 10-fold compared with their baseline levels.

This finding was in direct contrast to the much more

modest changes in serum testosterone they had observed.

It suggests that although much of the androstenedione

Figure 5 Serum testosterone levels during 12 hours of frequent blood

sampling in postmenopausal women. Circles represent control subjects receiving

no supplement, triangles those receiving 50 mg of androstenedione,

and squares those receiving 100 mg. Source: Adapted from Ref. 18.

that is absorbed after oral administration is converted to

testosterone, it is then immediately further metabolized

to inactive compounds in the liver. The investigators confirmed

this hypothesis by directly measuring the concentration

of one of these inactive metabolites (testosterone

glucuronide) in the serum of these subjects. As expected,

they found that testosterone glucuronide levels increased

by 500% to 1000% (as opposed to the 34% increase in biologically

active serum testosterone after a single 300-mg

dose of oral androstenedione). Together, these findings

demonstrate the effectiveness of the liver in inactivating

steroid molecules when taken orally.

PHARMACOKINETICS AND HORMONAL EFFECTS OF

ANDROSTENEDIONE IN WOMEN

Since the initial report of androstenedione administration

in two women in 1962 (6), research into the effects of the

supplement has focused largely on the hormonal response

to oral administration in young men. Between 2002 and

2003, however, two studies on women were published.

The first of these studies examined the effects of a single

dose of 0, 50, or 100 mg of androstenedione in postmenopausal

women (18). The findings of this study were

surprising. In contrast to the effects observed in men, even

these low doses increased testosterone levels significantly

in women (Fig. 5).

Also, unlike the results seen in men, estradiol levels

were unaffected by androstenedione administration.

In the other study, 100 mg of androstenedione was administered

to young, premenopausal, healthy women.

Similar to postmenopausal women, these subjects experienced

significant increases in serum testosterone levels

after androstenedione administration (estradiol was

not measured) (19). Importantly, in both of these studies,

the peak testosterone levels achieved by the older and

younger women taking androstenedione were often significantly

above the normal range. Together, these results

predict that the physiological effects of the supplement

may be different in men and women, as might their potential

toxicities. To date, however, there have been no

published reports investigating the long-term physiological

effects in women.

ADVERSE EFFECTS AND TOXICITY

Ever since the publicity surrounding androstenedione exploded

in 1999, many reports in the lay press have focused

on the potential dangerous side effects. Nonetheless,

with the exception of a single case description of a

man who developed two episodes of priapism in the setting

of androstenedione ingestion (20), there have been no

published reports of androstenedione-associated serious

adverse events. This fact should be only partially reassuring,

however, because androstenedione’s prior classification

as a dietary supplement (as opposed to a drug)

allowed manufacturers to avoid responsibility for rigorously

monitoring any potential toxicity of their product.

It is well known that oral administration of certain

testosterone derivatives can cause severe liver diseases,

and anabolic steroid use in general is associated with

anecdotal reports of myocardial infarction, sudden cardiac

death, and psychiatric disturbances (“roid rage”).

Nonetheless, despite androstenedione close chemical

similarity to these substances, it is important to note that it

is not a potent anabolic steroid nor does it have a chemical

structure similar to those specific compounds that cause

liver problems. Thus, the potential of androstenedione to

cause these particular serious side effects appears to be

limited. Of more pressing concern to clinicians are the

possible long-term effects in specific populations. In clinical

trials, the supplement was generally well tolerated,

though several studies did report that it reduces high density

lipoprotein (or “good cholesterol”) levels in men.

Importantly, however, even the longest of these studies

lasted only several months. It thus remains quite possible

that androstenedione use, especially at high doses,

could cause subtle physiological changes over prolonged

periods that could directly lead to adverse health consequences.

In men, for example, the dramatic increase in

estradiol levels observed with androstenedione administration

could, over time, lead to gynecomastia (male breast

enlargement), infertility, and other signs of feminization.

In women, because the supplement increases testosterone

levels above the normal range, it could cause hirsutism

(excess body hair growth), menstrual irregularities, or

male-like changes in the external genitalia. In children,

increases in both testosterone and estrogen levels could

cause precocious puberty or premature closure of growth

plates in bone, thereby compromising final adult height.

PURITY OF COMMERCIALLY AVAILABLE
ANDROSTENEDIONE

During its period of over-the-counter availability, androstenedione

was available from multiple manufacturers

and could be purchased as a tablet, capsule, sublingual

tablet, or even a nasal spray. Often, it was combined

with other products that claimed to limit its potential side

effects (such as chrysin, for example, which is purported

to decrease androstenedione’s conversion to estrogens).

Because the manufacture of dietary supplements was not

Androstenedione

Source: From Ref. 21.

subject to the same regulations as pharmaceuticals, the purity

and labeling of androstenedione-containing products

were often inaccurate. Catlin and colleagues, for example,

reported that urine samples from men treated with

androstenedione contained 19-norandrosterone, a substance

not associated with androstenedione metabolism

but rather with the use of a specific banned anabolic

steroid (21). Further investigation revealed that the androstenedione

product used contained a tiny amount of

the unlabeled steroid “19-norandrostenedione.” Though

the amount of 19-norandrostenedione was not physiologically

significant, it was enough to cause a “positive” urine

test for illegal anabolic steroid use when tested in the standard

fashion. In fact, it is precisely this type of contamination

that may have explained increases in positive tests

for 19-norandrosterone among competitive athletes in the

past decade. Additionally, it is now common for athletes

who test positive for norandrosterone or other androgenic

metabolites to point to dietary supplement contamination

as the potential explanation.

Catlin and colleagues also analyzed nine common

brands of androstenedione and showed that there was

considerable variation and mislabeling among products

in terms of both purity and content (Table 1).

REGULATORY STATUS AND DETECTION

Androstenedione was available over-the-counter from

1994 (when the DSHEA was passed) until it was reclassified

as an anabolic steroid by the Anabolic Steroid Control

Act in 2004. It is important to note that this reclassification

came without any evidence that androstenedione increased

muscle mass or strength, which was the previous

legal definition of an anabolic steroid. Virtually all sports

organizations, including the National Football League, the

National Collegiate Athletic Association, and the International

Olympic Committee, have banned androstenedione.

Despite these prohibitions, detection of androstenedione

has not been standardized. Specifically, the method

used most often to detect testosterone use, measurement of

the urinary testosterone-to-epitestosterone ratio, has not

proven to be reliable in establishing androstenedione use

(22). Further study is still needed to define novel testing

procedures that are able to detect androstenedione use

reliably.

CONCLUSIONS

Androstenedione is a steroid hormone, which, until 2004,

was a popular over-the-counter dietary supplement. Since

then, however, it has been classified as an anabolic steroid,

and hence a controlled substance. It is purported to increase

strength, athletic performance, libido, sexual performance,

energy, and general quality of life. Studies indicate

that when taken orally by men, small doses are

converted to potent estrogens and larger doses to both

testosterone and estrogens. Comparatively, there appears

to be a much more physiologically important increase in

estrogens compared with testosterone in men. In women,

the effects are reversed. Studies have thus far failed to

confirm any effect on muscle size or strength, though the

dosing regimens were modest. Although documentation

of adverse side effects among users of androstenedione is

scarce, there is considerable concern over potential longterm

toxicity, especially in women and adolescents.

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