Prohormone

A prohormone refers to a committed precursor of a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. Though not hormones themselves, prohormones amplify the effects of existing hormones. Examples of natural, human prohormones include proinsulin and pro-opiomelanocortin.

For peptide hormones, the conversion process from prohormone to hormone typically occurs after export to the endoplasmic reticulum and often requires multiple processing enzymes. For example, proinsulin is processed by PC 1/2, PC 3, and carboxypeptidase E to afford insulin. Proamylin, which is cosecreted with proinsulin, this requires the above three factors and an amidating monoxygenase. Though commonly misdescribed as such, Vitamin D3 is not an example of a prohormone or a hormone.^[1] The word prohormones has taken on a new sense due to the presence of specific oral medications designed for athletes to affect hormone levels. For small molecule hormones, the conversion is often one step, and is often used to regulate hormone levels.

Prohormones of testosterone and other androgenic steroids

Current legal status of prohormones and other substances with anabolic effects in most Western countries

In the last two decades, pro hormones have also been used by bodybuilders, athletes, and nonmedical users of anabolic steroids and other hormones to refer to substances that are expected to convert to active hormones in the body. The intent is to provide the benefits of taking an anabolic steroid without the legal risks, and to achieve the hoped-for benefits or advantages without use of anabolic steroids themselves. Many of these compounds are legal to manufacture, sell, possess and ingest eliminating the legal problems associated with schedule III anabolic steroids. The typical definition of "prohormone" includes a steroidal molecule that has the opposite molecular structure to testosterone on either the 3a/b position or the 17b position. Testosterone has a ketone group on the 3 carbon and a hydroxyl on the 17b carbon. A steroid with modifications away from testosterone in one or both of these areas is commonly referred to as a "prohormone". These enzymatic changes occur with the body's bidirectional enzymes.^[2][3]

A typical prohormone is intended to be a precursor of an anabolic steroid like testosterone, which is taken in order to boost the body’s available hormone supply. These precursors are intended to be converted to full, active hormones via an enzymatic process that occurs during metabolism, typically resulting in the addition of whichever atoms happen to be missing from the chemical structure of the compound.

Prohormones are used mainly by athletes looking to increase size, strength, endurance, reduce recovery time or add lean body mass. They are most often used for increasing muscle mass or reducing body fat levels. Life extension groups are also increasingly using prohormones as a means of hormone replacement therapy, as an alternative to prescription drug use. Additionally there is a movement to use prohormones of androgens to help offset the damaging effects of environmental estrogens on the body. Chemical endocrine disruptor agents like bisphenol A are becoming recognized as having the ability to skew the androgen to estrogen ratio. This skewed ratio can have many adverse effects on men, including sexual performance, impotence and other testosterone dependent body functions.

The use of prohormones has become popular among bodybuilders, since the effects can be similar (though normally much less drastic) to those achieved through the use of synthetic anabolic steroids, including gains in muscular strength and hypertrophy. There are currently many companies manufacturing prohormone products for this purpose.

Prohormones have the same side effects as anabolic steroids, and are dependent upon the user as to which side effects one might experience. Some side effects are acne, hair loss, breast tissue enlargement, and prostate swelling; however, these are specific to each type of prohormone, and reports of side effects are usually minimal.

The potential for these side effects does exist, but it can be reduced if one uses proper precautionary measures such as post cycle therapy (PCT). Generally, if a person is genetically predisposed to a side effect it will occur (i.e.: if someone has a history of male pattern baldness in the family, it could be assumed that this could be a side effect experienced if prohormones are used)

On October 22, 2004, President Bush signed into law the Anabolic Steroid Control Act of 2004 (118 Stat. 1661).^[4] The bill was written to become effective in 90 days, which was January 20, 2005. This legislation places both anabolic steroids and some prohormones on a list of controlled substances (a new type of "regulatory control").^[4][4]Statutory definition of Anabolic steroids: “The term 'anabolic steroid' means any drug or hormonal substance, chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids and dehydroepiandrosterone)”. The Act also lists substances called prohormones, qualifying them as anabolic steroids, yet these substances were mainly included in the list due to the generalization of the definition of anabolic steroids which makes it currently impossible to synthesize any further substances linked with testosterone for the needs of athlete supplementation.^[5]

Prohormones added to the list of schedule III anabolic steroids

The 108th Congress amended the Controlled Substances Act to include anabolic steroids and to add in information about steroids and steroid precursors. This amendment is sometimes called the Anabolic Steroid Control Act of 2004. The first thing this amendment did was insert a definition of anabolic steroids as follows: “The term ‘anabolic steroid’ means any drug or hormonal substance, chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids and dehydroepiandrosterone).”^[5] Apart from the definition, the document enumerates the presently known prohormones:

• Androstanediol (3β,17β-dihydroxy-5α-androstane and 3α,17β-dihydroxy-5α-androstane)
• Androstanedione (5α-androstan-3,17-dione)
• 1-Androstenediol (3α,17β-dihydroxy-5α-androst-1-ene)
• 4-Androstenediol (3β,17β-dihydroxy-androst-4-ene)
• 5-Androstenediol (3β,17β-dihydroxy-androst-5-ene)
• 1-Androstenedione (5α-androst-1-en-3,17-dione)
• 4-Androstenedione (androst-4-en-3,17-dione)
• 5-Androstenedione (androst-5-en-3,17-dione)
• Norandrostenediol (19-nor-4-androstenediol or 3β,17β-dihydroxyestr-4-ene)
• 19-Nor-4-androstenediol (3α,17β-dihydroxyestr-4-ene)
• 19-Nor-5-androstenediol (3β,17β-dihydroxyestr-5-ene and 3α,17β-dihydroxyestr-5-ene)
• Norandrostenedione (19-nor-4-androstenedione or estr-4-en-3,17-dione)
• 19-Nor-5-androstenedione (estr-5-en-3,17-dione)
• Any salt, ester, or ether of a drug or substance listed above

Please note that this list contains examples and it is not a closed list - any other compound, which affects testosterone, according to the definition is an anabolic steroid under U.S. law.^[5]

Common types of prohormones prior to 2004 anabolic control act

4-androstenedione

• Converts to: testosterone via 17bHSD
• Characteristics:
  • Research indicates a conversion rate of about 5.9%, which means that of the amount taken orally, 5.9% is converted to testosterone.
  • Relatively high rate of aromatization to estrogens, and consequently higher risk of side-effects such as gynecomastia brought on by excessive estrogen formation.
  • Exhibits significant androgenic properties, which may result in side effects such as male pattern baldness, acne, and enlarged prostate.
  • A recent study looking at the long-term effects of androstenedione use in rats for their entire life cycle showed no increase in mortality over a control group, showing that androstenedione and presumably all prohormones without chemical modifications to be reasonably safe.

4-androstenediol (4-AD)

• Converts to: testosterone via 3bHSD
• Characteristics:
  • Conversion rate of about 15.76%, almost triple that of androstenedione, due to utilization of a different enzymatic pathway.

19-norandrostenedione

• Converts to: nortestosterone (also called nandrolone) via 17bHSD
• Characteristics:
  • Only slightly less anabolic than testosterone.
  • Low rate of aromatization to estrogens.
  • Low occurrence of androgenic side effects.

19-norandrostenediol

• Converts to: nortestosterone vis 3bHSD
• Characteristics:
  • Low occurrence of androgenic side effects.

1-androstenediol (1-AD)

• Converts to: 1-testosterone, a 5-alpha reduced 1-ene steroid; 1-testosterone is better (although rarely) described as dihydroboldenone, the 5-alpha reduced version of the naturally occurring steroid boldenone
• Characteristics:
  • Cannot aromatize to estrogen either directly or through any of its metabolic products. However, 1-Testosterone, being a 5-alpha reduced steroid, is highly androgenic; it is very similar to Dihydrotestosterone (DHT). Many side effects associated with excessive levels of DHT, including male pattern baldness, testicular shrinkage, benign prostate hypertrophy and acne can occur with 1-AD usage. (Journal of Organic chem. vol, 27 1962 iss.1)

1,4-androstadienedione (1,4 AD)

• Converts to: boldenone
• Characteristics:
  • High level of oral bioavailability.
  • Low rate of aromatization to estrogens (approximately half that of testosterone).
  • Low occurrence of androgenic side effects.

1-testosterone (1-T)

• Characteristics:
  • similar to testosterone except instead of a 4,5-double bond it has a 1,2-double bond.
  • has about 20% oral bioavailability compared with less than 5% for testosterone
  • non-aromatizing to estrogen or DHT
  • has irritative properties making it too painful to inject, and has extremely bitter taste, making transcutaneous topical solutions the only practical human delivery method. It was commercialized this way in the United States before 2005, when it became illegal together with many other prohormones.
• History: 1-T was discovered in the 1950s, explored as a potential anabolic product by the pharmaceutical company G.D. Searle, but not commercialized at the time due to difficulty in delivery.
• Also considered a steroid

"Designer steroids" and adulterated supplements.

In view of a total ban from 2004, manufacturers cannot launch next anabolic compounds, presently they are interested in substances that are related to hormones, but do not affect testosterone. These include estrogen derivatives e.g. 13-ethyl-3-methoxy-gona-2,5(10)-dien-17-one (SUS500, Ethyl Methoxy Gona) methasteron (so called Superdrol or S-Drol) and many others, sometimes called "designer steroids". Such compounds although harmful, do not infringe the Anabolic Steroid Control Act because they do not have any impact on the testosterone level. Owing to the same reason, they did not assist in building muscle and are not applicable in supporting - it is typical that the descriptions of these compounds try to manipulate the chemical concepts, but do not even mention the possibility of raising testosterone – because they do not even have such a potential.^[6] That is why, in practice, agents labeled with these compounds of this type turned out to be falsified, because they contained, not declared in the composition, typical anabolic steroids.

After the publicity of the fraud in the media^[7] many manufacturers lost the trust, and the U.S. health authorities began to eliminate suspicious products. The research carried out by state laboratories confirmed that "designer steroids" are, in fact, pharmaceuticals like Metandienone, Stanazolol, Methylstenbolone, Boldenone, Turinabol, DHT, Oxandrolone, added to supplements in a random manner.^[8] Supplements with different names and described ingredients could have the same steroid (e.g. Halodrol i S-drol, Ergomax LMG - desoxymethyltestosterone) and sometimes supplements with similar names could have different ingredients (e.g. Finabolic, )^[6]

Regulation in the United States and Europe

Following the introduction of the Anabolic Steroid Control Act, labeling products derived from plant extracts with the help of chemical symbols of organic substances found in these plants or creating names for these substances which referred to prohibited anabolic substances became a popular marketing practice employed by American manufacturers. No analogical act targeting athlete supplementation is in force in the European Union; however each country has its own regulations concerning substances with medicinal properties. Due to the above, one can come in contact with the sale of supplements with names identical to or resembling those questioned by the RDA in the United States (S-DROL, HALODROL, etc.). Laboratory controls indicate that products which declare to include prohormones, prohibited in the USA, in fact contain “classic” anabolic steroids of the previous generation.^[9] Many consumers in Europe did not know that it was illegal produce prohormones in the USA after the year 2004 and thought that were consuming various versions of the previously acclaimed supplement, while in fact consuming steroids of unknown origin. In situations like ones described above the purchaser of this fake substance knows neither the type nor the dosage of the ingested hormone, and thus cannot plan a safe gastro-protective regime or supplementary treatment. The consumer also cannot gain access to information concerning the possible long-term consequences of treatment with the unspecified hormone. This has led to the popularity of special forums on which consumers could share their experiences with the substances, yet the fake products could have radically different components, despite similar descriptions and names. Supplement manufacturers who have made a name for themselves and want to remain on the market are currently elaborating anabolic products based on natural substances (usually plant derived). In Europe these products are called prohormones.

Producers who still want to offer supplements supporting the hormonal balance can still employ the natural compounds. Known in the field of prohormones Patrick Arnold (the one who introduced 1-AD and the first prohormones) is currently working on ursolic acid, on the other hand in Eastern Europe manufacturers launch supplements based on buteins,^[10]- natural compounds considered as the strongest aromatase inhibitors.^[11]

References