Het Anabolenboek

Willem Koert
Aede de Groot

Wageningen, 14/09/2006

1. Anabolic Steroids

Aede de Groot, Willem Koert

Living organisms consist for the biggest part of compounds in which the main element is carbon (symbol C). There has been a time when chemists thought that only living organisms could make carbon compounds and the name Organic chemistry for the chemistry of carbon compounds originates from this time.

For about one and a half century we know however that chemists can make carbon compounds also very well in laboratories. Organic chemists characterize this ability as organic synthesis and in the last century millions of carbon compounds have been synthesized. Meanwhile the name Organic chemistry has been maintained for the chemistry of carbon compounds.

Living organisms convert these organic compounds in biological processes into many other substances. which are used as construction material for the body, for the production of energy and for maintenance of life. It is the Biochemistry that studies these processes and tries to unravel the why and how of their occurrence.

The boundary between organic chemistry and biochemistry is not always clear because the carbon compounds which are transformed in living systems are similar to those in laboratories and also the reactions that they undergo are similar. The compounds and reactions in living organisms are however much more complicated that those in laboratories.

Chemists always have been interested in organic compounds from nature. These compounds, termed natural products, play an important role in everyday life. We need them as food and use them as flavours and fragrances, colouring substances or medicines. The chemistry of natural products is situated in between organic chemistry and biochemistry and is often referred to as bio-organic chemistry.

Steroid hormones belong to this large group of natural products and the androgenic-anabolic steroids are members of this group of steroid hormones. They are biosynthesized in the testes, the ovaries and the adrenaline cortex. Androgenic-anabolic steroids are chemical messengers. The bloodstream transports them to different tissues in the body, where their physiological effects are mediated by the androgen receptor. This receptor is present in many target tissues and the complex of the androgenic-anabolic steroid with the androgen receptor induces there many specific actions.

Testosterone (see Figure 1) is the most prominent example of the androgenic-anabolic steroids. In adult males its complex with the androgen receptor is responsible for maintaining libido, production of sperm, increase of muscle mass, strength and bone mineral density, the so-called anabolic effects. In other tissues enzymes convert testosterone into dihydrotestosterone through transformation of the double bond in the left ring of testosterone to a single bond (see Figure 1). The complex of dihydrotestosterone with the androgen receptor is responsible for mediating the androgenic effects like body hair and beard growth, acne, and in elder man, pattern baldness and enlargement of the prostate.

Enzymatic removal of the methyl group between the first and second ring in testosterone leads to the female sexhormones estrone and estradiol (see Figure 1). Together with progesterone they are responsible for the characteristic female sex properties. Their complexes with the estrogen and progesterone receptors mediate the development of the vagina, the uterus, the breasts, the increase of fat tissue and the regulation of the menstruation cycle.

Figure 1

All these important functions of steroid hormones have aroused great interest in the pharmaceutical industry. For a complete understanding of the role and function of steroid hormones, many disciplines have to cooperate.

- - To begin with, analytical chemists have to discover the new compounds in Nature, isolate them, purify them and elucidate their structure. Synthetic organic chemists also can make new compounds in the laboratory.

- - Once the structure of the steroid hormone is known, bigger quantities are necessary to enable further studies of their biological properties. Chemists can obtain these bigger quantities from nature by isolation from for instance wastes from slaughter-houses or by total synthesis in a laboratory. The latter has the advantage that also structural variants of the steroid hormone can be synthesized and tested for their biological properties.

- - When these bigger quantities of the steroid hormone are available physiologists can carry out more extensive physiological tests. Biochemists try to find the receptor and try to elucidate the working mechanism.

- - Pharmacists investigate the effects in the body and develop a suitable way to administer the compound. A dose response curve is determined.

- - Physiologists and endocrinologists investigate the working mechanism of the steroid hormone on tissue and organ level and investigate side effects.

- - Finally doctors undertake extensive investigations of the steroid hormone in hospitals and after a period of all together about six years, health authorities either permit the compound as a medicine or reject it.

- - In the meantime, at least when the perspectives remain promising, chemists and technologists develop a process for the production of the steroid hormone on large scale in a chemical plant. Tablets or injections then will be available when authorities have given permission to use them.

It will be clear that all these investigations are extremely expensive and take much time. Usually only powerful pharmaceutical companies can mobilze enough manpower, knowledge, time and money to approach these problems successfully. The development of a new medicine takes about 6 years and costs about one billion euro.

Chemists and pharmacists pay much attention to improve the biological activity of new medicines. The desired physiological effect of the compound has to be obtained with the smallest possible dose and side effects have to be minimized or preferably have to be absent. The research on androgenic-anabolic steroids has for instance been focussed for a long time on a better separation of their androgenic and anabolic effects. Until now these efforts have been only partly successful, which is understandable since all physiological effects rely on their interaction with the same androgenic receptor.

Usually many chemical variants of a new anabolic steroid are synthesized and tested to find such an optimized compound. At the end only one or two of these compounds reach the market and the rest disappears in the archives of the pharmaceutical company. Often investigators publish their results in the scientific literature and the investigated compounds are not commercialized. The literature about steroids is especially rich in the sixties and seventies of the former century and many studies about compounds and their activities have been published in that period. Many smaller companies nowadays profit from this knowledge. They hope to learn from it how to make small changes in compounds but to maintain most of the desired properties. In this way the so called designer anabolics are developed.

Many of these new designer anabolics are not patented and have not yet appeared on the lists of forbidden doping compounds. Producers of these compounds often claim that the new products are legal, which means that they are not yet forbidden. Legal is however not the same as healthy or effective and many of these compounds may be risky for the user. Doctors did not carry out the very expensive medical tests, which are necessary for new medicines and usually there are also no studies available about their supposed beneficial effects.