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Testosterone Conversion into Dihydrotestosterone

Testosterone Conversion into Dihydrotestosterone and Estradiol, Estrogen Aromatization, Beneficial Effects of Estrogen and Muscle Regeneration

SNAPSHOT: Many steroid hormones have very similar structures, and one form can be converted into others via complex and highly specific enzyme-mediated reactions. These reactions differ among body tissues to produce steroid hormones in a “tissue-specific” manner and elicit a variety of physiological effects. Regarding anabolic steroids, testosterone itself can exert biological effects, or it can be converted into other steroids such as estrogen or an analog named Dihydrotestosterone.

When considering the effects of androgens it is critical to think of testosterone both as a hormone and a prohormone. The mechanisms by which dozens of steroid hormones (including androgens) are interconverted are highly complex. In addition, testosterone can exert biological effects itself, or it can be converted into different hormones in specific tissues to elicit a variety of functions. Generally, testosterone is produced from the precursor androgens androstenedione (catalyzed by the 17β-hydroxysteroid dehydrogenase [17β-HSD]) and androstenediol (catalyzed by 3β-HSD). It then functions directly, or is converted further into Dihydrotestosterone (DHT) or estradiol. DHT and estradiol then activate the androgen receptor and estrogen receptor, respectively. These processes and their biological significance regarding the actions of anabolic steroids and the building of skeletal muscle mass are discussed below.

Dihydrotestosterone Conversion

SNAPSHOT:The testosterone analog DHT is not produced naturally in skeletal muscle. Nevertheless, DHT is much more potent than testosterone. This is in part because it has a higher affinity for the androgen receptor, and in part because DHT-androgen receptor complexes are more stable than are testosterone-androgen receptor complexes. Together, this makes the DHT-androgen receptor complexes less prone to dissociation and degradation.

The conversion of testosterone into DHT is catalyzed by an enzyme named 5α-reductase. This enzymatic reaction occurs only in specific tissues (including the adrenal gland, prostate, central nervous system, liver, and testes), and approximately 5% of testosterone is converted into DHT. Importantly, skeletal muscle samples harvested from human cadavers 12 hours after death revealed that 5α-reductase activity was not detectable in muscle. In addition, the enzyme 3α-hydroxysteroid-dehydrogenase, which catalyzes the irreversible conversion of DHT into 3α-androstanediol, exhibits a very high level of expression and activity in skeletal muscle; therefore, endogenous DHT concentrations are very low. As such, endogenous DHT is unlikely to play an important role in the growth and development of skeletal muscle.

Although the two androgens are very similar structurally, DHT and testosterone exhibit different functions, and DHT is 3–4-fold more potent than testosterone. This increased potency is thought to be in part because DHT has a much higher affinity for the androgen receptor (AR) than does testosterone, and in part because DHT-AR complexes are more stable than are DHT-T complexes.

Estrogen Aromatization

SNAPSHOT: The use of anabolic steroids increases estrogen levels via different pathways. For example, testosterone can be converted into estrogen in tissues including the testis, skeletal muscle, bone, and adipose tissue. In addition, increased levels of testosterone increases the amount of bioavailable estrogen by displacing it from a serum carrier named SHBG, because testosterone has a higher affinity for SHBG than does estrogen. Together, these factors cause abnormally elevated estrogen levels in individuals with high testosterone (such as males that use anabolic steroids), which can lead to unwanted side effects such as breast development, elevated fat mass, and increased water retention. Therefore, many people who take anabolic steroids also receive anti-estrogen agents or aromatase inhibitors (which inhibit the reaction that produces estrogen from testosterone) to reduce or prevent the incidence of these side effects. However, individuals taking these agents should be aware that estrogens also exert beneficial effects, which are discussed further below, and that abnormally low estrogen levels can be highly dangerous if too many anti-estrogen agents or aromatase inhibitors are taken.

Testosterone is converted into estradiol (an estrogen) by the enzyme aromatase in males. Aromatase is expressed in various tissues, including the testes, skeletal muscle, bone, adipose tissue, and throughout the brain and central nervous system. In the context of building muscle mass, aromatase activity and the presence of estradiol is complex, particularly in males. Elevated estrogen levels and a decreased ratio of testosterone to estrogen in males are associated with a variety of unwanted side effects, including increased adiposity (the accumulation of fat tissue), water retention, and breast development (known medically as gynecomastia); therefore, many individuals using anabolic steroids also administer anti-estrogen agents. However, estrogens play important roles in several processes during building muscle mass; therefore, there is a very fine line between exploiting the beneficial effects of estrogen on muscle development and removing unwanted side effects. In this section we discuss the positive and negative roles of estrogens and anti-estrogens in building muscle mass and anabolic steroid use.

First, it is important to understand that the use of anabolic steroids increases estrogen levels by several pathways in addition to the direct aromatization of testosterone into estrogen. Under normal circumstances, the ratio of testosterone to estrogen in males is approximately 100:1. As mentioned above in the section "The Regulation of Testosterone Production”, circulating levels of testosterone are regulated tightly by a negative feedback pathway. This means that the repeated administration of high doses of steroids effectively “shuts down” endogenous testosterone synthesis. In addition, physiological endocrine homeostasis, whereby the body seeks to maintain the balance between estrogen and testosterone levels, also leads to increased estrogen production.

The majority of both estrogen and testosterone circulate in the human body bound to sex hormone binding globulin. However, SHBG has a much higher affinity for testosterone than it does for estrogen. The elevated levels of estrogen that occur commonly after the administration of anabolic steroids increases the production of SHBG in the liver, decreasing the bio-availability of testosterone further and exacerbating the dysregulated estrogen to testosterone ratio.

Therefore, increased estrogen levels and estrogen aromatization can be a significant problem in males who use anabolic steroids. Although aromatization is highly dependent of the structure of the steroid (for example, those based on the structure of Dihydrotestosterone rather than testosterone are not susceptible to the activity of aromatase because DHT is not a natural substrate for this enzyme), all anabolic steroids have the capacity to increase estrogen levels via other pathways. As such, many males who use anabolic steroids also receive anti-estrogen compounds and/or aromatase inhibitors to reduce or prevent unwanted side effects. For example, the breast cancer treatment tamoxifen is used by some individuals who use anabolic steroids because it functions as an estrogen receptor antagonist. Examples of aromatase inhibitors include Cytadren and Arimidex; however, the use of high doses of these compounds can cause hypoestrogenism (abnormally low estrogen levels). Therefore, the balance between preventing the side effects of anabolic steroid that are caused by aromatase/high estrogen levels and the beneficial effects of estrogen on building muscle mass (see below) must be considered carefully.

The Physiological Beneficial Effects of Estrogens

SNAPSHOT: There are several beneficial effects of estrogens that individuals who take a combination of anabolic steroids and anti-estrogen agents or aromatase inhibitors should be aware of. Specifically, estrogens are important for muscle repair and regeneration, prevent muscle weakness in females, and stimulate increased protein synthesis during resistance training. In addition, estrogens enhance energy production by increasing the activity of the enzymes that are important for generating energy in skeletal muscle, and further studies have suggested that estrogens are important for the normal metabolism that is important for building muscle mass. Estrogens also regulate the production of various proteins that play a key role in building muscle mass, such as growth hormone. Although other potential effects have been described, such as on the androgen receptor, sufficient convincing and supportive evidence is currently lacking.

Estrogens and Muscle Regeneration

In spite of the various negative effects of increased estrogen levels on individuals trying to build muscle mass described above, estrogen and estrogen-based hormones exert many anabolic effects that are beneficial in people wishing to build muscle mass and reduce fat mass. Perhaps most importantly, estrogens exert multiple effects to promote muscle healing and regeneration, which are both critical for building muscle mass successfully. For example, estrogen-based hormone replacement therapy in females prevents muscle weakness and the accumulation of fat in muscle, and also increases protein synthesis during resistance training. In addition, estrogens modulate the activation and proliferation of a specific muscle population known as satellite cells to help regulate muscle repair and growth. Importantly, several scientific studies have revealed that estrogens increase muscle strength, stiffness, and contractile function in mice lacking ovaries, and also decrease inflammation. However, other studies have suggested that estrogens decrease muscle strength and running activity in female mice.

Estrogen and GH/IGF-I

One important effect of estrogens is to regulate the expression of growth hormone (GH) and insulin-like growth factor-I (IGF-I), which play important roles in muscle development, repair, and regeneration. Briefly, GH is a hormone that is produced in a pulsatile manner by the anterior (front) part of the pituitary gland. In addition to exerting direct effects in muscle, such as promoting muscle mass, it also stimulates the production of IGF-I in various tissues including the liver, adipose tissue, and skeletal muscle. IGF-I then modulates a variety of physiological process, including protein synthesis and muscle repair. However, the exact roles of estrogens on GH and IGF-I expression and/or activity are complex, and some of the data available are contradictory. Breast cancer patients treated with the antiestrogen tamoxifen exhibited decreased serum IGF-I levels , suggesting that the presence of estrogens increases IGF-I levels. Therefore, it might be beneficial in individuals trying to build muscle mass. However, several other studies demonstrated that estrogens inhibit GH/IGF-I expression and/or signaling . In addition, estrogens have been used to treat acromegaly (GH excess) since the 1930s because they lower GH levels, suggesting that the use of aromatase inhibitors might increase GH concentrations by decreasing estrogen levels. Therefore, the data are complicated, and it is possible that estrogens might have different effects on GH and IGF-I and/or in different tissues. Nevertheless, studies have confirmed that the administration of testosterone increases local IGF-I production in skeletal muscle, although it is unclear if this was associated with increased serum estradiol levels.

Estrogen and the Androgen Receptor

One potential beneficial effect of estrogens in males trying to build muscle mass is related to effects on the androgen receptor. Specifically, a study performed in 1984 administered estradiol to castrated rats (which have their testes removed and so lack endogenous testosterone), which resulted in a 480% increase in binding between exogenous androgens and the androgen receptor in pelvic muscle, but not skeletal muscle. However, it is unclear whether these effects were due to the increased production or decreased degradation of the androgen receptor. In addition, the absence of a comparable effect in skeletal muscle brings the relevance of these findings to anabolic steroid use into question. Although it is known that estrogen and the estrogen receptor help maintain skeletal muscle mass, any relevance between this and the androgen receptor remains controversial.

Inhibitors

The efficient production and use of energy is one of the most important processes when building skeletal muscle mass. The energy required for muscle development is provided by aerobic metabolism (which uses oxygen to convert carbohydrates, fat, and protein into adenosine triphosphate [ATP], the primary energy source in muscle), and anaerobic metabolism (glycolysis, which breaks down glucose without a requirement for oxygen). Some studies have suggested that the absence of estrogen inhibits glucose uptake during exercise, which is critical for muscle contraction and hence building muscle mass. In addition, the activity of enzymes that are important for energy generation was decreased in rodents lacking ovaries, whereas the addition of exogenous estrogens restored normal metabolism. Therefore, estrogen appears to be very important for energy generation and utilization in skeletal muscle.

Glossary

  • ↩Prohormone – a precursor to an active hormone.
  • ↩Aromatization – the process that converts testosterone into estrogen.
  • ↩Homeostasis – a state in which the conditions within a system, tissue, cell, or body are relatively stable and constant.
  • ↩Bio-availability – the amount of a drug, hormone, or agent that is free and/or able to exert its physiological effects.
  • ↩Substrate – a protein or molecule that is acted on by a specific enzyme.
  • ↩Contractile function – the ability of muscle to contract.
  • ↩Pulsatile – growth hormone is secreted in “pulses”; therefore, release occurs on and off over time, and is not constant.
  • ↩Exogenous – an agent or substance from outside the body.