Testosterone increased during the 20's


On June 1, 1889, Charles Édouard Brown-Séquard announced to the French Biological Society in Paris that he had discovered a fountain of youth and had already tried it on himself. The then 72-year-old neurologist and physiologist (Fig. 2), temporarily professor at Harvard University in Cambridge (Massachusetts) and since 1878 holder of the chair for experimental medicine at the Collège de France, repeatedly had a liquid extract from animal testicles - from dogs and guinea pigs - sprayed. Since then, he claimed, he has felt physically stronger and mentally fresher; He told the audience straight away that his problems with constipation had also been resolved and that he could urinate again in a high arc.

Despite the skepticism of some colleagues, he insisted on a direct connection between injection and effect. Even today, many experts tend to believe in a placebo effect (in order to work as described, the medication would have had to be much more intense). Nevertheless, Brown-Séquard is considered to be a founder of endocrinology, the theory of the formation and effect of hormones: his assumption that substances from testicles can increase or replace their function later proved to be essentially correct.

His merit is to have recognized that the lack of certain physiological regulators secreted in the body - the term hormone was first coined in 1905 after the Greek horman (drive, stimulate, set in motion) - can be counteracted with extracts from animal organs. He thus followed up on the fundamental research results of his predecessor at the Paris chair: Claude Bernard (1813 to 1878) had developed the concept of the inner milieu and in 1855, in connection with studies of the function of the liver and pancreas in the sugar balance and digestion, the idea of ​​an inner milieu Secretion introduced.

Thus began partly absurd, partly increasingly refined attempts at hormone treatments. The research culminated in 1935 with the synthesis of testosterone, the main hormone produced by the testes. It is formed both in the male and - to a lesser extent - in the female organism. On the one hand, it has an androgenic effect, i.e. it promotes the development of the male reproductive organs and secondary sexual characteristics, characterizes the psyche in a typical way and is involved in sperm maturation; on the other hand, it has an anabolic effect by increasing protein biosynthesis from dietary protein - anabolism. Chemically, it's a steroid (see box on page 85).

Since then, a wide variety of artificial anabolic-androgenic substances have been produced, which are derived from testosterone or related compounds - an ambivalent success. Because of their two main properties, they offered therapeutic benefits as well as tempting abuse.

As early as the 1940s, word got around among bodybuilders and competitive athletes that such synthetic hormones accelerate the build-up of muscles and enable more intensive training (Fig. 1). In particular, those derivatives of natural substances that are relatively little androgenic (virilizing), but have a strong anabolic effect and are also only slowly degraded, were used en masse. Doping with anabolic steroids has long been banned and, like the use of other non-physiological performance-enhancing agents, has been controlled at international competitions since 1966; but there is still a gray area from which a black market with immensely high sales profits.

The other, lesser-known use is the legitimate one for therapeutic purposes. Longer than for doping, anabolic steroids with the weakest possible virilizing effect have been used on the one hand to increase the synthesis of endogenous proteins in the case of debilitating diseases, and on the other hand artificial androgens to compensate for a deficiency in natural hormones or for the so-called hormonal castration of patients with breast cancer. At first, testosterone and related substances also seemed to become standard remedies for men against age-related symptoms of decline, but this was mainly prevented by the side effects of certain preparations: changes in behavior, functional impairment of the liver, and sometimes impotence and infertility; it can also make prostate and testicular cancer worse. Women who try to counteract some hormonally influenced diseases with androgens often get a deeper, rough voice, male body hair including a beard and an enlarged clitoris.

However, the more pharmacology and medicine progress, the more difficult it becomes to keep legitimate use and abuse clearly separate. More and more differentiated knowledge is gained about both the risks and the possible uses. An important aspect is to weigh the side effects and benefits of a medically indicated application against each other. Intensive research is also being carried out on steroids as contraceptives for men; and some doctors continue to promote artificial sex hormones to maintain physical performance, libido, and self-esteem in aging men.


Magic and organotherapy

Brown-Séquard had distributed his testicle extract free of charge to practitioners who wanted to test the effect. In many countries attempts have been made to cure various diseases with it, be it tuberculosis or cancer, diabetes or paralysis, gangrene, anemia, arteriosclerosis, even flu, hysteria or migraine. Basically, the age-old magical idea that one must treat the same with the same still had an effect: Similia similibus is a principle of homeopathy founded by Samuel Hahnemann (1755 to 1843), who worked in Leipzig, Koethen and Paris. It has been historically documented since antiquity that, for example, components of human or animal hearts were prescribed to strengthen courage, brain tissue to cure dementia, and all imaginable, mostly unsavory parts of organs, body fluids and excretions - bile, blood, urine, Faeces, intestines, placenta, bones, teeth, horn and feathers - against other ailments of all kinds.

The sexual organs and their secretions have always had a special place in this bizarre pharmacy. In ancient Egypt, for example, medical powers were attributed to the testicles. According to Pliny the Elder (23 to 79), the donkey penis in oil as well as the penis-like clitoris of spotted hyenas, which in turn were coated with honey, were considered aphrodisiacs in ancient Rome. Likewise, the legendary ancient Indian healer Sushruta, whose teachings were included in the medical collection "Ayurveda", which was codified around 500, recommended the consumption of testicular tissue against impotence. Even in a German pharmacopoeia, the "Pharmacopoea Wirtenbergica", published in 1754, there are wondrous things to be read about the effectiveness of horse testicles and marine animal reproductive organs. And it was not only in earlier times that it was difficult to distinguish between myth and reality in sexuality.

Two thoroughly serious researchers were inspired by Brown-Séquard's ideas to conduct experiments that seem at least dubious today: The Austrian physiologists Oskar Zoth and Fritz Pregl (who received the Nobel Prize for his work in analytical chemistry in 1923) tested on their own whether liquid extracts from bull testicles required muscle strength strengthened and suitable for athletes; They used an ergograph to record fatigue curves of their middle fingers.

According to an article by Zoth published in 1896, they found a marked effect on the "neuromuscular apparatus". The two researchers explicitly excluded what many of their current colleagues believe, namely that they had only observed a placebo effect, and therefore said that the method should be tried out on athletes, also in the service of scientific progress - that was the first, so to speak Sports medicine proposal for hormone treatment for doping.

Meanwhile, other scientists were looking for the active ingredients of testicular extracts. In 1891 the chemist Alexander von Poehl succeeded in isolating spermine phosphate in the form of crystals. He realized that the substance was also present in the body in other ways, in men and women, and concluded that it increased the alkalinity of the blood, which was therefore probably able to carry more oxygen.

When hemoglobin binds oxygen, there is actually a slightly alkaline environment and a slightly acidic environment when it releases it again. It was however a mistake by Poehls to have discovered a "dynamogenic", vitalizing substance in the sense of Brown-Séquard and thus to have underpinned his theses. It is now known that although spermine and the related spermidine specifically shape the smell of sperm (they are bound to the phosphate groups of the nucleic acids in it), they are widespread polyamines - they are probably found in all microorganisms, plants (roots, leaves and fruits) and animals . Poehls' conjecture has proven to be correct insofar as spermine and spermidine have growth-promoting properties; In addition, in 1992 Ahsan U. Khan of Harvard University in Cambridge (Massachusetts) and his colleagues found evidence that spermine helps protect nucleic acids from oxygen radicals.

Apparently, in 1912, the first attempt was made to transfer the hormone-supplying organ instead of an extract in the event of a loss of sexual functions. It was then that a man in Philadelphia received an alien human testicle inserted; the intervention is said to have been, as it was later said, "apparently technically successful". The following year, Victor D. Lespinasse operated on a patient in Chicago who had lost both testicles. He cut the replacement organ, which he had taken from a donor under anesthesia, into three slices, which he then implanted. Four days later, the heroic practitioner noted, "the patient had a strong erection and pronounced sexual desire; he insisted on leaving the hospital in order to satisfy it". Even after two years he is said to have been potent; Lespinasse spoke of an "absolutely perfect" procedure.

Perhaps the most daring and ruthless of these surgeons was Leo L. Stanley, a doctor at the San Quentin, California state penitentiary, who had many avid recipients and unwilling donors available: since 1918, he has implanted testicles of newly executed inmates of all ages; quite a few of the operated on stated that they had regained their potency. And due to a "lack of human material", Stanley began using testicles from billy goats, goats, deer and boars, which supposedly fulfilled their function just as well. The number of his transplants ran into the hundreds. The word-of-mouth propaganda soon turned it into a panacea - not only the impotent and senile sought help from him, but also asthmatics, epileptics, diabetics, tuberculosis and mental patients and those affected by gangrene. Stanley maintained that he had not observed any harmful side effects; "The animal testicle material" exerts "clear effects", also "in the case of obscure pain", and promotes "general physical well-being".

From today's perspective, this early organotherapy - a kind of forerunner of the fresh cell therapy developed by the Zurich urologist Paul Niehans (1882 to 1971), in which tissue fragments or organ fragments from animal embryos or freshly slaughtered young animals are injected - is right on the verge of quackery . At the time, Stanley's work was reputable enough that he could publish it in the renowned journal "Endocrinology". But, like Brown-Séquard, he complained that charlatans pretended to be able to restore manhood and that "pirates of medicine" sailed half-blindly over this "barely mapped sea of ​​research", some of whom had primarily the financial gain in mind. He had no qualms about his own approach; He considered the highly dubious findings to be convincing. It was the epoch when the Russian-French surgeon Serge Voronoff made fortunes with his controversial transplants of "monkey glands".

Nevertheless, medical historian David Hamilton also classifies Voronoff as a serious researcher - because endocrinology was still in its infancy in the 1920s and medical ethics committees were a rarity. At that time, journals regularly warned of "miracle healers", "cures against everything with glandular cocktails" and "extravagant therapeutic excursions", but they also indicated cautious optimism. Considering the low level of knowledge at the time and the various temptations to develop new procedures, one should rather speak of a medical tightrope walk than of perceived vertigo.


The discovery of testosterone

The targeted search for a specific substance with androgenic properties was already underway. A. Pézard described in 1911 that the crest of a castrated rooster grew when it was injected with testicular extract, proportionally to the dose. For two decades, the capon comb test and animal models of a similar kind became a tried and tested means of testing the androgenic effects of various substances isolated from large quantities of animal testes or human urine.

Finally, in 1931, the biochemist Adolf Butenandt (1903 to 1995), who worked in Danzig, Berlin, Tübingen and Munich, was the first to obtain androgen from 15,000 liters of urine by police officers to obtain 15 milligrams of androsterone (to which testosterone is broken down in the body). That the testes contain an androgenic factor ten times more potent - testosterone - was found out in the following years.

In the race for this hormone, with the help of competing pharmaceutical companies, three research groups took part:

- On May 27, 1935, Kàroly Gyula David and Ernst Laqueur, who worked together with the Organon company in Oss (Netherlands) (Laqueur, pharmacologist in Ghent and Amsterdam, long as scientific advisor), submitted to the "Zeitschrift für Physiologische Chemie" together with colleagues "The classic work" On crystalline male hormone from testes (testosterone), more effective than androsterone prepared from urine or cholesterol ";

- On August 24th, Butenandt and Günter Hanisch, who were behind the Schering AG in Berlin, moved into "Reports of the German Chemical Society" with the publication "About the conversion of dehydro-androsterone into D4-androsten-ol- (17) -on- (3) (testosterone); a way to display testosterone from cholesterol "according to; and

- On August 31, the article "About the artificial production of the testicular hormone testosterone (Androsten-3-on-17-ol)" was received by "Helvetica Chimica Acta", the author of which was the Croatian-Swiss, in Utrecht and from 1929 in Zurich active chemist Leopold Ru`´zi`´cka and the Swiss chemist Albert Wettstein, who at the same time announced the application for a patent on behalf of Ciba-AG (which merged with Geigy in 1970).

For their research in the field of hormone chemistry - among other things, they had also identified female sex hormones - Butenandt and Ru`´zi`´cka (1907 to 1974) received the Nobel Prize in Chemistry in 1939. Of course, Butenandt was only able to receive it after the end of the Hitler regime; German citizens had not been allowed to do so since 1936.


Androgens as pharmaceuticals and doping agents

The battle for the synthetic testosterone and derivatives market had begun. Clinical testing was already underway in 1937, both with testosterone propionate, a modified molecule (like other testosterone esters, it can also be used as a depot preparation, while testosterone itself only has a very short-term effect), and with methyltestosterone, which could be administered orally and at a slower rate Is broken down as testosterone (but has strong side effects on the liver). Initially, these investigations were hardly less targeted than the early transfers of testes or their extracts. However, the hormonally active substances were initially mainly given to young and adult men with underdeveloped gonads or impaired hormone function, so that the secondary sexual characteristics such as deep voice or beard growth matured or remained, as well as patients who had a kind of male climacteric - a still elusive and controversial phenomenon - has been attested, which includes impotence, among other things.

Even women were soon given synthetic androgens, which act as antagonists of the female steroid hormone estrogen. Indicators were excessive menstrual cramps as well as excessive and long bleeding, pain in the breasts and also estrogen-dependent breast cancer, because for about 100 years doctors had observed that metastatic breast cancer regressed in certain cases when the hormonal balance was shifted. As far as we know, every third breast cancer is hormone-dependent. In the case of advanced tumors after the menopause, hormonal counter-therapy is the second or third measure after surgical removal.

In the forties, when less was known about the connections, patients of all ages were subjected to this therapy. It was also observed that androgens can relieve cancer-related pain and increase appetite, weight and well-being, even if the tumor growth itself cannot be stopped; In addition, many of the women to whom such preparations were applied under the skin in crystalline or dissolved form in high doses reported recurring or increased libido.

Androgens have not become a standard therapy for female sexual disorders, although some doctors in the United States, and perhaps even more so in Great Britain and Australia, prescribe them for it. Not only then, as now, did some patients find the artificially greatly increased sex drive disturbing - the masculinization of the external appearance was also a side effect that could hardly be accepted. Whether or not it persists after the medication is discontinued has been heatedly debated in the specialist literature.

Based on the idea that testosterone neutralizes the effects of estrogen, attempts were made to use it to cure male homosexuality, so to speak (testicular transplants had thought of this as early as the 1920s). For example, in 1940 the magazine Endocrinology read: "It is evident that homosexuals have higher estrogen levels" and the conclusion was that "the chemistry of sex hormones in a homosexual constitution is different from that of normal men". Another work from 1944 described "a series of clinical studies on organotherapy" on eleven "openly homosexuals who, for various reasons, wanted treatment". The real motives become clearer, however, when the authors write in the following of four of the patients that they were "prepared to undergo organotherapy under duress" - in one case after a court ruling, in the other three on parental orders.

The measure, for which there were no control attempts, was a failure. Because five of the test subjects complained about an increase in libido, the researchers admitted that it was possible that "the treatment of active (aggressive) homosexuals with androgens tended to intensify the sex drive" instead of reducing it. "In certain cases," they insisted, "the results are simply too good for unjustified pessimism to diminish the value of this treatment."

As early as 1935, Charles D. Kochakian, a pioneer in research into synthetic hormones, pointed out that androgens also increase the build-up of protein-containing body substances and that they could perhaps stimulate regeneration and growth processes in a number of clinical pictures. The medical literature of the early 1940's contains much discussion of this relationship. From then on, there is increasing speculation as to whether this might not make it easier to build muscle during training and thus increase athletic performance. In 1941 an endurance test of men taking testosterone gave a positive result. Another scientist considered in 1944 whether "the age-related decline in labor force could not be influenced by artificially increasing the sex hormone level".

The subject soon appeared in popular science literature. In particular, a book by the writer Paul de Kruif, published in 1945, may have contributed to the fact that athletes began to dope with hormones. As was later told, bodybuilders on the American West Coast tried it around 1950. A little later a Soviet trainer of weightlifters (Fig. 1) freely reported about anabolic steroids experiments.

By the mid-1960s, the prescription for medicinal muscle-building seems to have got around among supervisors and athletes in other strength sports, and eventually this form of doping became common in more and more Olympic disciplines, not only among competitive athletes, but even among American students and college students. Students. The number of those who abuse anabolic steroids in the USA is estimated to be a million - including many recreational bodybuilders who only want to make an impression with their figure. There were enough ways to circumvent the bans introduced in competitive sports or to deceive them during controls; The responsible committees did not always take systematic and harsh measures.


Other medical applications

Some medical indications for male steroid hormone treatment have persisted since the early days of androgen therapy. Mostly effective testosterone esters are used for days to weeks. The majority of the patients are still men with hypogonadism, in whom the sexual organs are not or only poorly developed and the secondary sexual characteristics are not properly expressed, another group of men with normal to low testosterone levels in the serum who are impotent for other reasons, and a third group of boys severely retarded development in which one tries to stimulate growth and initiate puberty (a low dose promotes the longitudinal growth of the bones, a high dose inhibits it). It has also become routine to support the treatment of children with a deficiency in growth hormone (somatotropin).

Because anabolic steroids stimulate the formation of red blood cells - erythropoiesis - they became the treatment of choice for various forms of anemia when bone marrow transplants and treatment with synthetic erythropoietin (the hormone that stimulates blood formation) were not possible. For a long time until the mid-1980s psychiatrists prescribed them for depression, melancholy and psychoses with autistic states of confusion.

Towards the end of the Second World War, attempts were made to use such substances to counteract the severe decline of the victims of concentration camps, which often seemed difficult to stop because of the chronic illnesses of a physical and mental nature. War wounded were also treated in this way in order to rebuild them; And even today, severely burned patients, those who have been operated on who recover poorly, and cancer patients who have to undergo radiation therapy are often given androgens.

It has recently also been investigated whether AIDS sufferers who are very emaciated, become weaker and weaker and suffer from muscle wasting, respond to anabolic steroids. The first studies are promising: patients generally feel better; Strength, appetite, and weight appear to be increasing.

In connection with the search for an anti-baby pill for men, thought has also been given since the late 1970s about how to intervene in the complex hormonal feedback loops between the brain and sex glands, which control testosterone and semen production. If the androgen blood level is artificially increased, for example due to testosterone esters, the testes should, at least ideally, cease their function completely and resume when the preparation is discontinued.

To this end, the World Health Organization carried out an extensive international study at ten medical centers. According to the 1990 report, anabolic steroids do indeed appear to be useful as contraceptives; the physical side effects, it says, were minor and temporary. It is noteworthy that the doses tested were probably higher than those that helped Canadian sprinter Ben Johnson to win the Olympic Games in 1988, which was subsequently revoked (Fig. 3). In the case of general use as a contraceptive, the medical arguments put forward against doping anabolic steroids in sport would hardly be tenable.

In the late 1980s, more researchers started looking at hormonally helping aging men. Some justified this with increasing life expectancy, others with preliminary studies, according to which growth hormone also seems to improve constitution and well-being in otherwise healthy old people. After 1990, several pilots were undertaken with men with low to normal testosterone levels who were over 54 years old. Overall, the result was positive. Muscle mass and physical strength increased; In some cases the bone loss also seemed to decrease, so that the risk of fractures might be reduced. As the test subjects reported, libido and sexual activity increased. Spatial imagination and word memory improved.

Because many doctors now consider hormone replacement for women during and after the menopause to be the right thing to do, they are likely to advocate a comparable measure for men. Reports in the mass media suggest that society would be ready to do so, as it has generally positive effects here.

Perhaps such treatment will be standard practice in generally healthy men ten years from now. The development towards this should already favor the increasingly demanding notions of quality of life. When, for example, the American National Health Institute in Bethesda (Maryland) suggested studies on the benefits of androgens against physical complaints and depression in older men in 1992, they also called for clarification as to whether the aging process itself should not be regarded regularly as a deficiency disease in need of therapy. Geriatrician John B. McKinley, director of the New England Research Institute in Watertown, Massachusetts, made an ironic prediction: "I don't believe in the midlife crisis in men. Although I don't think there is any evidence for it, epidemiological, physiological or clinical so it will exist as a syndrome in 2000. There are very strong commercial interests that aging men - like postmenopausal women - receive hormonal treatment. "

When economic pressure and societal aspirations come together, there is of course the danger that the medical profession will not pay sufficient attention to dubious side effects and overestimate the medical benefits of a compliant prescription of androgens. McKinley and his colleagues warned in the Journal of Urology in 1994 that there could be a market of 18 million men seeking treatment for impotence in the United States alone, which, given the lack of correlation with androgen levels, raises serious concerns. Even if this use of synthetic steroid hormones disappointed, it would hardly prevent them from being used as general anabolic agents and to restore libido. Society is increasingly seeing aging as a medical problem in its own right; this solidifies the idea that men suffer a kind of climacteric like women and that something must be done about it. The way in which such a general change in attitudes enters into medical doctrine, in turn, will influence the general assessment of what is physiologically normal. Obviously we tend to regard it more and more as legitimate that the human organism is driven to ever higher mental and physical achievements.

Bibliography

- hormones. The chemical messengers of the body. By Lawrence Crapo. Spectrum of Science Publishing Company, Heidelberg 1986.

- The Male Hormones. By P. de Kruif. Harcourt, Brace and Company, 1945.

- Anabolic-Androgenic Steroids. By Charles D. Kochakian. Springer, 1976.

- The Monkey Gland Affair. By David Hamilton. Chatto and Windus, 1986.

- Mortal Engines: The Science of Performance and the Dehumanization of Sport. By J. Hoberman. Free Press, 1992.

- Anabolic Steroids in Sport and Exercise. Edited by Charles E. Yesalis. Human Kinetics Publishers, Champaign (Illinois), 1993.


From: Spektrum der Wissenschaft 4/1995, page 82
© Spektrum der Wissenschaft Verlagsgesellschaft mbH

This article is contained in Spectrum of Science 4/1995