Vidyya Medical News Service
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Volume 6 Issue 73 Published - 14:00 UTC 08:00 EST 13-Mar-2004 Next Update - 14:00 UTC 08:00 EST 14-Mar-2004
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FDA white paper: Health effects of androstenedione

Summary:

Androstenedione and related molecules, if given in sufficient quantities and for sufficient duration, are likely to cause androgenic (and thus anabolic) or estrogenic effects in humans. Although these compounds possess at most weak intrinsic androgenic activity, they are prohormones for both androgens (testosterone) and estrogens. The biochemical evidence supporting the effect of androstenedione to raise circulating levels of testosterone and estrogens is strong. This, in conjunction with the known potential for site-of-action direct conversion of androstenedione to testosterone, leads to a conclusion of a direct relationship between risk of androgenic or estrogenic effects of treatment and dose and duration of treatment. In particular, androstenedione and related molecules consumed in sufficient quantities to have any anabolic effects will confer androgenic and estrogenic risks, although risks may also be present with consumption that is not sufficient to produce obvious anabolic effects.

Children and adolescents are particularly vulnerable to irreversible effects of androstenedione via its conversion to active sex steroids. These effects include disruption of normal sexual development, specifically virilization in girls associated with severe acne, excessive body and facial hair, deepening of the voice, permanent enlargement of the clitoris, disruption of the menstrual cycle, and infertility. The conversion to estrogens can cause feminization of boys, with breast enlargement and testicular atrophy. In girls, exposure to excess estrogens may confer long-term increased risk for breast and uterine cancer. Finally, in boys and girls, the combined effects of excessive androgens and estrogens can induce premature puberty, early closure of the growth plates of long bones, resulting in significant compromise of adult stature.

Background: steroid hormone metabolism and actions of androgens and estrogens

All steroid hormones derive from cholesterol as the initial substrate. In specialized cells and tissues (e.g., adrenal gland, testis, ovary), cholesterol delivered via circulating lipoproteins is converted, through a series of biochemical steps, to testosterone and estradiol, as well as to other potentially active steroid hormones. These hormones are released into the circulation and travel to target tissues where they have their physiologic action. There are numerous low-abundance intermediates in the biochemical pathway to these end products, and these include androstenedione.

Androstenedione ("andro") and its derivatives, including androstenediol, norandrostenedione, norandrostenediol, are believed to possess little intrinsic activity as hormones, but andro and its derivatives can be readily converted to active androgens (male hormones, possessing anabolic activity) and estrogens (female hormones). After ingestion and absorption into the blood stream, they may be metabolized (converted) in liver and, perhaps more importantly, at peripheral sites of action (like muscle) to testosterone and subsequently aromatized (another metabolic conversion) to estradiol (potent estrogen) in adipose (fat) tissue. These molecules may thus be considered prohormones of both potent androgens and estrogens. That is, consumption of these intermediate molecules can "drive" production of active sex hormones and thereby effect desired (i.e., muscle growth) and undesired (see below) changes in those ingesting them.

As far as what is measured in blood (which at best is only partially predictive of actual response to exogenous andro), the metabolic conversions of these molecules in the liver after ingestion and absorption appear to occur variably from person to person of the same sex and to differ more dramatically between the sexes. As a rule, based on the available studies, summarized below, the relative increases in testosterone are greatest in women, both young and old, because of the normally low levels of testosterone production in females. Conversely, the relative increases in estrogens are greatest in men, who normally produce little estrogen. On the other hand, peripheral tissue-based (non-liver) conversion of andro to testosterone, for example in muscle, is expected to be independent of sex, as the enzyme necessary for this conversion is present in the tissues of both men and women.

The ultimate hormonal effects of andro are expected to differ in men and women, if only because of the differences in their normal hormonal milieus and in their responses to excess androgens or estrogens. So-called androgenic and estrogenic responses to exogenously administered compounds and to endogenous hormones are very well understood and delineated in standard textbooks of medicine and endocrinology. There is compelling evidence supporting a reasonable conclusion that, in a dose-related fashion, the androgenic and/or estrogenic effects of these prohormones, over time, will have multiple systemic adverse consequences that increase the risk of a striking number of serious adverse events in children and adults of both sexes.

Effects of administered androstenedione on levels of androgens and estrogens in of men and women:

There is direct evidence of conversion of andro to testosterone through hepatic and peripheral conversion with aromatization of testosterone to estrogen in adipose tissue, and there is strong, though indirect, biochemical evidence of likely site-of-action conversion of circulating andro to active sex hormones to mediate its diverse tissue effects. We gather from reports in the media that anecdotal evidence of anabolic response is plentiful, though available only by word of mouth, e.g., within the athletic community. Relevant studies are summarized below:

Effects in men: predominant elevations in estrogens

King et. al. (JAMA 1999; 281:2020-2028) enrolled 20 healthy males, aged 19-29, in an 8-week resistance training program and randomized (1 :1) to placebo vs. androstenedione 100 mg three times daily during weeks 1, 2, 4, 5, 7, 8. In a separate group of 10 men, the effects of androstenedione 100 mg in a single dose on levels of various hormones was studied.

Using this regimen, neither the single 100 mg dose nor extended administration of 300 mg daily measurably affected serum levels of testosterone. By contrast, serum levels of estradiol and estrone were raised by ~50% by 2 weeks of therapy with 300 mg daily. There were no effects of androstenedione 300 mg daily on strength, muscle fiber size, lean body mass, fat mass. Androstenedione treatment did reduce HDL-C (good cholesterol) relative to placebo.

The authors make the point that the higher doses of androstenedione that may be taken by those hoping for performance enhancement are likely to lead to greater elevations in serum estrogen concentrations, with potential adverse effects (see below).

Leder et. al. (JAMA 2000; 283: 779-782) treated healthy men aged 20-40 years with androstenedione 100 mg daily (n=15), 300 mg daily (n=14), or nothing (n=13) for 7 days.

Though there was no effect at the 100 mg daily dose, there was a mean ~35% increase in testosterone in the serum (integrated over 8 hours) at the 300 mg daily dose. Additionally, serum estradiol levels (integrated over 8 hours) were elevated 42% and 128%, respectively at the low and high doses of androstenedione, respectively.

The authors point out that with higher doses and more frequent administration as may characterize use by those interested in performance enhancement, "...it is likely that some individuals may experience sustained and larger increases in testosterone levels…" In addition, they speculate based on their data that differential metabolism to androgens and estrogens across individuals may predispose some to more androgenic responses and others to more estrogenic responses to androstenedione administration. Adverse effects of androgen or estrogen excess are discussed below.

Effects in Women: predominant elevations in androgens

Leder et. al. (JCEM 2002; 87: 5449-5454) studied the effects of single oral doses of androstenedione (10 women each received either 0, 50, or 100 mg) on serum levels of androstenedione and sex steroids in healthy postmenopausal women.

After androstenedione administration, serum levels of estrone over 12 hours were elevated up to ~115% at the 100 mg dose relative to control. Testosterone levels over 12 hours were elevated up to ~450% relative to control at the high androstenedione dose. Estradiol levels were not elevated relative to placebo. The authors speculate that the elevations in testosterone with androstenedione administration in these women could have adverse effects (see below).

Kicman et. al. (Clinical Chemistry, 2003; 49:167-169) studied the effect of a single dose of androstenedione 100 mg on plasma testosterone over 24 hours in 10 healthy young women in a 2-period crossover study.

Plasma testosterone levels integrated over 24 hours were 16-fold greater than control. The authors also noted that the plasma testosterone concentrations observed were "similar to those encountered in abuse of testosterone for anabolic purposes, the peak of the mean concentrations being at the upper end of the reference interval for men ." These authors as well express concern about the potential adverse effects of elevated sex hormone levels in people taking androstenedione.

Peripheral activation of absorbed andro

Finally, the data on effects of oral andro on circulating levels of testosterone and estrogen, while clearly indicative of the potential for hepatic conversion to these active steroids, likely does not, in fact, account for all of the actions of these products. Specifically, muscle, as well as other known target tissues of anabolic steroids, contains abundant enzyme that converts circulating andro (known to be readily absorbed by mouth producing transient high levels in the blood) to testosterone, right at the site of action, without necessarily affecting circulating testosterone levels.

Listing of androgenic and estrogenic (potential) adverse effects of andro:

The following lists the well-known adverse effects of excess androgens (male hormones) and estrogens (female hormones). These adverse effects will occur to varying degrees based on potency of the administered hormone, dose, and duration of exposure. It is important to note that not all effects, be they deemed primarily cosmetic or serious health consequences, are fully or even partially reversible.

Androgenic

Acne/seborrhea (oily skin)
Hirsutism (excessive hairiness, particularly on the face and trunk, i.e., male-pattern)
Male pattern baldness
Deepening of the voice due to laryngeal hypertrophy
Clitoromegaly (abnormal, permanent enlargement of the clitoris)
Weight gain, altered fat:muscle ratios
Loss of female body contour
Altered menstrual cycling
Increased libido in women
Testicular atrophy
Reduction in HDL-C, potentially increasing risk of atherosclerosis
Alterations in coagulation
Edema (swelling of soft tissue of the extremities due to abnormal retention of fluid)
Erythrocytosis (increased red cell production, thickening the blood)
Obstructive sleep apnea (periodic slowing or cessation of breathing during sleep, a risk for combined heart and lung disease and death)
Fetal effects via transplacental transfer
Liver disease (a known problem with 17-alkylated anabolic steroids) including cancer
Increased aggressiveness

Estrogenic effects

Gynecomastia (breast enlargement in males)
Testicular atrophy
Impotence
Abnormal menstrual cycling
Endometrial hyperplasia (abnormal growth of the lining of the uterus, a risk for uterine cancer)
Blood clots
Glucose intolerance/diabetes
Hypertriglyceridemia (elevated fats in the blood, a risk for heart disease and pancreatic injury)

Effects of sex hormones generally (not restricted to androgens or estrogens)

Sex hormone related epilepsy
Migraine headache
Premature closure of growth plates of bone with reduction in height (mostly an estrogenic effect)
Precocious (early) puberty

Risks in children and adolescents

Children and adolescents are particularly vulnerable to irreversible effects of androstenedione via its conversion to active sex steroids. These effects include disruption of normal sexual development, specifically virilization in girls associated with severe acne, excessive body and facial hair, deepening of the voice, permanent enlargement of the clitoris, disruption of the menstrual cycle, and infertility. The conversion to estrogens can cause feminization of boys, with breast enlargement and testicular atrophy. In girls, exposure to excess estrogens may confer long-term increased risk for breast and uterine cancer. Finally, in boys and girls, the combined effects of excessive androgens and estrogens can induce premature puberty, early closure of the growth plates of long bones, resulting in significant compromise of adult stature.

Conclusion:

As stated above, if taken in sufficient doses, andro products will have anabolic effects. Those taking sufficient quantities of these prohormones to effect anabolism (the goal of the athlete in training) are by definition at risk for androgenic (anabolic steroids are androgenic, both effects being mediated through the androgen receptor) as well as estrogenic effects, all as a result of metabolic conversion of the precursor hormones to active sex steroids. However, even some of those not taking sufficient quantities for sufficient durations to provide obvious performance enhancement or muscle growth may still be at risk for adverse effects of androgen and/or estrogen excess, regardless of age or gender.


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