Chapter One ‑ The Testosterone Story
Hormones have a long, exciting and chequered history, and that of testosterone is the longest, most exciting and most chequered. However its history is part of the problem in getting the Male Menopause accepted as a real condition, so lets look back to see where the maze of myths surrounding testosterone starts.
The word hormone was introduced in 1905 by a British physiologist, Professor Ernest Starling, in a lecture he was giving at the Royal College of Physicians in London. It was derived by two scholarly dons in Cambridge from the Greek verb hormao, meaning to put into quick motion, to excite or to arouse. He used it to describe the "chemical messengers" that were released into the blood‑stream by the body's ductless, or endocrine glands ( endon‑ internal + krino ‑ secrete)), such as the testis, thyroid, and adrenals, from the external (exo ‑ outside ) secretions of glands with ducts, the exocrine glands, such as those that produce saliva or tears. This heralded the birth of the science of hormones, or endocrinology, which lived up to its prophetic name by making rapid advances, which excited both the public and medical imagination and often aroused great passion and controversy.
Typically the history of any one hormone goes through four stages:
Firstly there is the observation that a gland or organ produces an internal secretion that has a general effect on the body.
Secondly, methods of detecting the internal secretion and measuring its effects are developed. This is usually initially by biological assay, seeing what action the preparation containing the hormone has on an animal or organ lacking it. Later chemical methods of measurement can be found.
Thirdly, the hormone is extracted from the gland or organ, and isolated in a pure form.
Fourthly, chemists define its structure and synthesise it.
We will see how testosterone was unique in being the first hormone to be recognised and measured, but because of the complexity of its molecule was relatively slow in being isolated and synthesised.
The observation that castration makes the eunuch, properly credited to primitive man, ushered in the dawn of hormone research. The fact that the testes are so easily removed in many species, including man, with dramatic, obvious and widespread consequences, have caused them to be described as the oldest key to the treasure trove of knowledge about hormones. To emulate one of Sir Winston Churchill's most famous sayings "Never in the field of human science was so much learned by so many by the removal of so little".
As the journalist Paul de Kruif put in his brilliant book on "The Male Hormone - A new gleam of hope for prolonging man's prime of life", printed in 1945, "From the beginning of human record, priests, saints, medicine men, farmers and sultans had been demonstrating how clear-cut, sure and simple it was to take the vigour of animals and men away. How? By removing their testicles."
He goes on to put the important question "Why didn't they reason that older men, losing their youth gradually, might also be suffering a slow, chemical castration taking place invisibly with the passage of time?". He then documents the slow march of the "Hormone Hunters" towards their goal of the "Rescue of Broken Men" and providing them with a "New Lease on Life" by isolating and then synthesising testosterone. However, his message has had to wait another fifty years to be heard.
Castration carried out on young boys was always recognised as preventing the onset of puberty, with lack of body hair or beard, more feminine fat distribution and a high pitched voice much valued in singing. This was thought to be worth the sacrifice by some Italian singers, the "castrati", or at least their managers, as graphically shown in the recent film "Farinelli, Il Castrato". Eunuchs were also known not to develop the male pattern of baldness, and to be less muscular.
Depending on how long after puberty it was performed, castration as well as making the eunuch infertile, reduced his sexual and other drives, but did not invariably make him lose erectile power. The more potent were used by Roman women, particularly when their husbands were away fighting for the Empire, for occupation without procreation.
Eunuchs were also known to be less competitive and aggressive. In the Byzantine period, for the thousand years from about 400 AD, the Empire was run increasingly by eunuchs, who were efficient, but predictably unadventurous and did what they were told. Similarly they played an important part in administration of the Imperial Court. They presumably knew their place, and posed no threat to the Emperor or those vying for power.
Similarly farmers of antiquity knew that castration could be used to fatten pigs, bullocks and cockerels to produce capons. The taming of wild animals for domestic purposes, and tempering the fiery nature of both horses and dogs, made the psychological effects of castration in other species equally apparent.
About four thousand years ago the Pen Tsao, the Chinese "Great Herbal" recommended the use of the semen of young men for treatment of sexual weakness in the elderly, a remedy doubtless popular with the wives of the impotent potentates.
In India, the Hindu Ayervedic system of medicine which developed from 1,400 BC onwards suggested the consumption of testicular tissue to treat impotence and obesity. It was also known at that time that hot baths could reduce fertility, which is still news over three thousand years later.
The great physician Hippocrates, who is said to have created medicine as both an art and science, lived during the golden age of Greek culture, being born in 460 BC and dying at over the age of ninety. His contemporaries included Socrates, Plato, Aristophanes, Euripides and Sophocles and yet of all these his reputation is probably the greatest. His is the moral medical code still used as the basis of medical ethics.
In the many classic writings noted by his pupils, he observed that gout does not appear before puberty, and that eunuchs do not develop it at all. Modern theory would suggest that the high levels of uric acid needed to cause this exquisitely painful condition of the joints, characteristically of the feet, come from the breakdown of the protein in the large muscle masses which testosterone produces in the postpubertal male. Another interesting observation he made was that women did not suffer from it till after the menopause.
He also knew that mumps could be followed by the inflammation of the testes known as orchitis, and then sterility. As described later, this, together with other viral illnesses such as glandular fever which cause testicular damage, can contribute to an early onset of the male menopause.
Nearly two thousand years ago, the Greek physician Pliny recommended eating animal testicles to improve sexual function. This remedy is still popular in many countries, especially Spain, where cooked bulls testes are served as the delicacy known as "Cojones". Not coincidently, this is also the Spanish word for courage. Unfortunately, any benefits obtained from eating such dishes are likely to be more morale boosting than hormone boosting, because though most of the body's supply of testosterone is made in the testes, it is rapidly exported to the rest of the body in the blood stream and there is little on site at any one time.
For example, when chemists first extracted the hormone from bulls testes in the early 1930's, it took several tons to produce a few hundred milligrams, the dose presently used one day's supply for a patient. This makes using this dietary source on a regular basis a daunting task! To make things worse, testosterone taken by mouth, unless it is in a special easily absorbed and stable form, is broken down in the liver, and never gets into the general circulation. This makes Pliny's treatment, though it must have sounded like a theoretically good idea at the time, practically useless apart from the doubtless strong placebo effect of many exotic remedies.
Later, the Roman physician Aretaeus, who gave the first detailed description of sugar diabetes, wrote "For it is the semen, when possessed of vitality, which makes us to be men, hot, well braced in limbs, well‑voiced, spirited, strong to think and act". He added the rider that "For when the semen is not possessed of its vitality, persons become shrivelled", which is a good description of the wrinkled skin and wasted muscles of the testosterone deficient male.
The message in Judaic medicine derived from the Old testament is that health is the gift of God and disease his wrath. This can therefore only be prevented by submission, atonement, prayer, moral reform or sacrifice, which are still unpopular remedies, and may be ineffective if left too late. It was also recognised that stress, disease, fatigue and starvation could reduce the amount of semen, which are all factors now known to lower testosterone levels, particularly in older men.
The Bible differentiated between those who because of diseased or undescended testes developed eunuchoid features, known in Egypt as those "castrated by Ra", the sungod, "sun‑castrates" and those castrated by man, "man‑castrates". When this was performed for religious reasons, the penis was often removed as well, a mutilation now only seen in some transvestites.
This differentiation is described in Matthew, Chapter 19, verse 12, Jesus is quoted as saying "For there are some eunuchs, which were so born from their mothers womb: and there are some eunuchs, which were made eunuchs of men: and there be eunuchs which have made them‑selves eunuchs for the kingdom of heavens sake." In the latter category, he appears to be referring to priests who achieved celibacy without going to such extreme measures.
These two types of testicular insufficiency or hypogonadism are recognised today as being either "primary", originating before birth, or "secondary", following some damage to the testis or interference with the production or action of testosterone. The Male Menopause falls within the secondary category, but occasionally there are elements of a primary cause which has been overlooked, as when one or both testes fail to develop or descend fully. Then there may be sufficient hormone to take the boy through an apparently normal puberty, and even become fertile, but in his thirties or forties the other factors which contribute to the andropause cause the limited supply of testosterone to become insufficient.
In India, those who renounce sexual activity because they believe it dissipates their spiritual energy, are known as bramacharya. In the Hindu tradition, it is one of the requirements of becoming a monk or Swami. A vegetarian diet may help them to make this difficult sacrifice and keep from straying from the spiritual path by decreasing the amount of cholesterol available for testosterone production.
This was confirmed in 1984 when a Swedish study showed that switching from a high to a low fat diet, particularly one high in polyunsaturates, lowered blood testosterone levels by 10%. This makes sense in evolutionary terms as the aggressive killer instinct of the hunter, red in tooth and claw, would be enhanced by the higher level of testosterone produced by having a higher fat, higher cholesterol diet than his more placid herbivorous prey.
The beadle of the orphanage in Dickens's story "Oliver Twist", Mr. Bumble, rebuked the undertaker who employed Oliver till he got into a fight with the words, "You never should have given the boy meat. Meat heats the blood". Perhaps the old man who for many years used to wander up and down Oxford Street in London with sandwich boards denouncing the "Passion Proteins" in meat and declaring that they led to war, may have stumbled onto an important truth.
Also the oestrogens present in many plants, phytoestrogens, can antagonise the effects of testosterone and give a more female type of fat distribution. The plants richest in these phytoestrogens are Soya, particularly tofu and miso, citrus fruits, wheat, liquorice, alfalfa, fennel and celery. which may be why some vegetarian yogi's have enlarged breasts, a condition known as gynaecomastia, and large abdomens. Pliny recorded 2,000 years ago that "Hempseed and chondrion make men impotent". Also, heavy beer drinkers, because of the phytoestrogens in hops, as well as the calories from the alcohol, and its damaging effect on the testes and liver, can show enlarged breasts, and "beer‑belly" as well as the erection problems described as "brewer's droop".
The most influential physician of Roman times, was Galen (130‑200 AD), who is considered the greatest medical man of antiquity after Hippocrates. He wrote more than 100 books whose influence carried on for more than fifteen hundred years, well into the renaissance period and beyond. However, he could also be thought of as the founding father of medical dogmatism in that his system was so authoritative and rigid that it almost completely stifled fresh ideas throughout that time.
In spite of this, Galen could be thought of as the forerunner of sex hormone theory and research. He describes how the "maleness" of men could cease with castration, and the "femaleness" of women with disease or ageing of the ovaries. He noted that these sexual characteristics were generalised throughout the body in all the species he studied, and were not purely genital, being seen for example in the lion's mane, the cox's comb and the boar's tusk. These remote and widespread effects are the characteristic features of hormonal action.
He also raised a key question of great importance to our thinking in relation to the reduction in vitality as well as virility seen in the menopausal male when he asked in his book "Peri Spermatos" (On The Seed), "What is, therefore, the cause, that castrates slow down in their whole vital capacity?". He remarks in this book that castrated animals lose not only the power to procreate, but also the desire to do so, as well as undergoing the characteristic changes in normal male fat and hair distribution, well recognised in eunuchs. In modern medical parlance, they show all the signs of testosterone deficiency.
It was only with the wave of radical new thinking that swept through Europe at the beginning of the sixteenth century that medicine broke free of the bondage imposed on it by Galen's words. This rebirth in both the arts and sciences was precipitated by two events. One was the fall of Constantinople in 1453 which ended the Byzantine empire and caused many scholars to move from there to Italy. As a result there was a revival of Greek medical thought in terms of the ideas and observations of Hippocrates, rather than the unquestionable dogma of Galen.
The other was the information revolution started by the printing of the Gutenberg Bible in 1454, which soon spread to the production of medical of medical texts. Let's hope that the new information revolution produced by the computer and the internet, which is starting to give us access to medical databases all over the world, will produce even greater advances in freedom of thought on all medical subjects including the andropause.
One of my heroes from this period is Paracelsus (1493‑1541), or to give him his full title, Aureolus Theophrastus Bombastus von Hohenheim, the most important medical thinker of the sixteenth century. As his name suggests, he was a Swiss, swashbuckling physician and chemist, who not only had the audacity to challenge Galen's ideas, but publicly burned his books. He revived Hippocratic thought and ideals in medicine and introduced many new ones of his own, especially in relation to thyroid disease. He died unloved and unrecognised by the medical establishment of his day, but left a legacy of original thought which became part of the active ferment which led to fresh medical thinking and experimentation on hormonal factors in health and disease. It influenced Charles Darwin who appealed to scientists to abandon intellectual "idolatry".
Paracelsus introduced a new vision of disease as a distinct explicable entity which could and should be treated, rather than the Galenic view that most conditions were untreatable and encouraged the population to bear with fatalistic resignation. For example he successfully introduced mercurials for the treatment of syphilis, the most feared disease of the sixteenth century, which was viewed in the same light as AIDS is in the present day. Perhaps we need to invoke the spirit of Paracelsus today to encourage wider discussion of topic of the Male Menopause.
How did the intelligent public view ageing in the male at that time? With his usual intuitive clinical accuracy, Shakespeare about four hundred years ago described in his play "As you like it" the seven ages of man and we can now recognise how each age is influenced by the effects of testosterone.
"At first the infant, Mewling and puking in the nurse's arms" (0‑10 years)‑ In the infant there is no real difference between the testosterone levels in boys and girls, though intrauterine differences have left their physical and emotional imprints.
"And then the whining schoolboy, with his satchel, And shining morning face, creeping like snail, Unwillingly to school." ‑ The surge of testosterone at puberty generates the rebellious male nature, as well as the increase in skin‑oil or sebum, which makes the skin shine and later in excess causes acne. The sexual characteristics of the adult male appear.
"And then the lover, Sighing like furnace, with a woeful ballad Made to his mistress' eyebrow." ‑ With the libido driven by the peaking levels of testosterone going full blast, and rampant priapic power available, mating and nest‑building activities normally tend to predominate.
"Then a soldier, Full of strange oaths, and bearded like the pard, Jealous in honour, sudden and quick in quarrel, seeking the bubble reputation Even in the Canon's mouth." ‑ Plenty of testosterone still making him belligerent and driving him through what is often a period of questing and hasty decisions, the "Mid‑life Crisis".
"And then the Justice, In fair round belly with good capon lin'd, With eyes severe, and beard of formal cut, Full of wise saws and modern instances;" ‑ With testosterone activity declining the scene is set for the Male Menopause to appear along with the fatty degeneration shared with the capon, showed by weight gain and the muscle deterioration seen first in the Elizabethan "couch potato's" expanding waistline.
"The sixth age shifts into the lean and slipper'd pantaloon, With spectacles on nose and pouch on side, His Youthful hose well sav'd a world to wide For his shrunk shank; and his big manly voice, Turning again towards childish treble, pipes And whistles in his sound." ‑ The decreasing free testosterone levels and lack of physical activity fail to maintain muscle mass, particularly in the legs, so that the calves and thighs shrink. Lack of testosterone also results in thinning of the vocal chords, which return to their prepubertal state giving a higher pitch.
"Last scene of all, that ends this strange eventful history, Is second childishness, and mere oblivion, Sans teeth, sans eyes, sans taste, sans everything." ‑ The old saying that what you don't use you lose comes sadly true at this stage of life, and there is considerable evidence to suggest that testosterone treatment can slow the rate of physical and mental deterioration in the final stages of life, and help men to maintain both the will and ability to continue active life till they drop. You now have the choice!
Shakespeare also wrote "Is it not strange that desire should so many years outlive performance?", a question which taxes the minds of doctors and their patients to this day. The answer could well be that lower levels of testosterone are needed to maintain libido than are required for potency and there are many complex circulatory factors involved in obtaining an erection, and well as the hormonal drive. The spirit is still willing often long after the flesh has weakened, though following repeated erectile failures, the desire tends eventually to fade also.
Eighteenth and Nineteenth Centuries
The dominant figure in experimental medicine in the eighteenth century was the English surgeon John Hunter (1728‑1793). Among his amazing range of original studies, were the experiments supporting his view that sexual characteristics "depend on the effects that the ovaria and testicles have upon the constitution". He obtained evidence for this statement in a variety of ways.
An interesting experiment on how the testes enlarged in the mating season in a variety of animals was carried out by killing and preserving a series of London cock‑sparrow's at monthly intervals from mid‑winter to spring. His students later reported Hunter's demonstration that "The one killed in December has testes not bigger than a small pin's head, the rest are gradually larger, the testes of the last, killed in April, are as large as the top of your little finger." We now know that this seasonal growth of the testes, with its accompanying surge in testosterone, is due to the longer days triggering the pineal gland at the base of the brain to switch off production of its "Hibernation Hormone" Melatonin. This in turn causes the pituitary gland to produce more of the hormones which rouse the dormant testes to spring fever pitch. It seems however that the bright city lights are now suppressing this seasonal cycle, and causing mating activity in cosmopolitan sparrow's all year round. Though in humans there is a slight surge in conception rates around holiday periods such as Christmas, there is a larger rise in late spring and early summer, so we retain this link between sunshine and sex.
What has not been sufficiently recognised is that he carried out transplantation experiments which showed that if the spur of a hen was transplanted to a cock, it would grow to the size of a cock's spur. He went on to demonstrate that if the small spur of a young cock was transplanted to a hen, it failed to grow at all. He also in 1771 transplanted cock's testicles into their abdomens, and observed that they continued to grow there, and into the same site in hen's, with some evidence of a masculinising effect.
However, he failed to publish his results, illustrating the truth of that old medical dictum "Publish or perish". It was not until over seventy years later, in 1849 that a German Professor at the University of Gottingen, Adolf Berthold, who knew of Hunters work, repeated the experiment, showing that capons could grow into normal cocks following testicular transplants. He wrote "They crowed quite considerably, often fought among themselves and with other young roosters, and showed a normal inclination to hens". In particular the transplants prevented atrophy of the comb, restoring this dramatic red crowning glory of the male of the species which signals his sexual maturity.
This was clear proof that the testis produced a substance which travelled in the blood to maintain the sexual characteristics of the adult male animal. This first well documented successful hormone replacement therapy inaugurated a century of attempts to use testicular extracts or implants to rejuvenate men. However, most of these attempts were either of doubtful effectiveness, mainly relying on the placebo effect of giving patients a novel form of treatment, or fraudulent confidence tricks based on the instinctive wish for a long and active life. It is difficult to this day to decide whether doctors offering rejuvenation treatments are "leading edge pioneers" or "medical buccaneers" who navigate "this poorly charted sea of medical research". Time and future research will tell.
One who must certainly be regarded as a pioneer, was the eminent neurologist and physiologist Charles Edouard Brown Sequard (1817‑1894). He had a distinguished career in France, where he had been the successor of the celebrated physiologist Claude Bernard at the Sorbonne in Paris, and had held posts in England and America, as well as being the first to demonstrate that the adrenal glands were essential to life.
However his colleagues became critical of his ideas when in 1869 he suggested that "the feebleness of old men is in part due to the diminution in function of the testicles". He also said that "if it were possible to inject, without danger, sperm into the veins of old men, one would be able to obtain with them some manifestations of rejuvenation at once with respect to intellectual work and the physical powers of the organism".
They were even more sceptical when in 1889, still actively researching his ideas at the age of 72 he announced at a learned gathering in Paris that he had mentally and physically rejuvenated himself with subcutaneous injections of extracts of the testicles of dogs and guinea‑pigs. Within three weeks the British Medical Journal had published a report on his lecture criticising his ideas and manner of their presentation. Under the heading of 'The pentacle of rejuvenescence" it said sarcastically that "The statements he made ‑ which unfortunately attracted a good deal of attention in the public press ‑ recall the wild imaginings of mediaeval philosophers in search of an elixir vitae". Similar responses to reports on the benefits of treating the male menopause are still prevalent over a hundred years later. Looking back, Brown‑Sequard's ghost might well comment "La plus ca change, la plus c'est le meme chose".
In England and America his results were said to be due to autosuggestion, or even hypnosis which was very fashionable in France at the time. He tried to counteract this notion by not giving the patients any idea of the results he was expecting, though any treatment by such a distinguished and imposing Professor must have had some placebo effect. He also sent his extracts to sympathetic colleagues in England and America, and though some reported good results, the general medical reaction in Britain to what rapidly became known as one type of 'organotherapy', treatment with glandular extracts or transplants, was hostile. However some of the critics were given pause for thought by work going on at the same time on the more obvious, reproducible and clear‑cut benefits of treating thyroid deficient, myxoedematous, patients with thyroid extracts.
In America however, the reactions to Brown‑Sequard's work was over‑enthusiastic, and the testicular extract was widely inflicted by charlatans on a gullible public as "The Elixir of Life" for every type of ailment from senility to tuberculosis. This and other "organotherapies" became even more fashionable because of the simultaneous introduction of "serotherapies" the use of sera and vaccines of animal origin for the prevention and treatment of infectious diseases.
Particularly in Victorian England studies in matters relating to sexual activity were considered "not quite nice", and unsuitable topics for research. Brown Sequard died a discredited man, who "made the blunder that put the male hormone in the scientific dog-house"as Paul de Kruif points out. Moralists were quick to jump on this failure in therapy, and as he documents, the ridicule that it brought to the whole field of research into the hormonal functions of the testis has lasted to the present day, and is an unfortutunate legacy. Brown-Sequard's mistake at the end of a long and innovative carreer in research was still being used by one learned professor as evidence against the existance of the Male Menopause even this year in a television documentary on the subject.
Even learned and very influential physiologists such as Sir Edward Schafer who wrote many papers and a book on "Endocrine organs" had a Freudian block about reproductive hormones, and in a lecture on "Internal Secretions" given to the British Medical Association in London in 1895, denied that the testes had any endocrine actions. It is amazing that so great a pioneer in other areas of endocrinology could have so complete a blind spot to the millennia of evidence to the contrary. However we hear echoes of this disapproval of research into the effects of testosterone treatment in relation to slowing the ageing process even now.
What also had a bad but unforeseen long term result in terms of the acceptance of testosterone treatment by doctors and the general public, was an experiment by two Austrian doctors in 1896 who claimed that testicular extracts of bull's testicles could improve the strength of their hand muscles. They concluded that "The training of athletes offers an opportunity for further research in this area". This report foreshadowed the damaging influence of steroid abuse by athletes on the medical and public image of testosterone treatment.
Though "organotherapy" using extracts of different glands, particularly the thyroid and adrenal, continued to be the subject of much speculation and experimentation, it soon became clear that testicular extracts were not sufficiently powerful to have the hoped‑for and much publicised effects originally claimed. This was because the minute amount of testosterone produced in the testes is continuously being swept away into the blood stream, and is not stock‑piled in the gland.
Remembering the work of Hunter and Berthold, doctors attempted what would be a difficult feat even nowadays, that of transplanting testicles from man to man. In 1912 and 1913 there were reports of the first two apparently successful operations in America. The second of these was performed by a Dr Victor D. Lespinasse of Chicago, who reported full restoration of libido and sexual function over a two year period in a man previously without desire and impotent from loss of both testes.
Though the Second World War held up endocrine research and held up communication between doctors working in different European countries for many years, there was an interesting report that the famous Danish surgeon Thorkild Rovsing carried out an experiment which seemed to indicate that testicular function might be important in relation to the circulation, as indeed Brown‑Sequard had claimed. After a young soldier had been killed in battle, Rovsing transplanted his testicles into an old man with gangrene, which then according to the case report healed completely.
In 1918 the resident physician in San Quentin prison in California, Dr. Leo L. Stanley, who had access to many fresh testicles "donated" by executed prisoners, started transplanting them into other inmates of various ages. Some of these regained their sexual potency, though how this was measured in the prison is unclear, and freedom is a great aphrodisiac. Two years later, because of "the scarcity of human material" even in that situation, he moved onto transplanting into his rapidly expanding patient population, the testes of rams, goats, deer and boars, which, perhaps suspiciously, seemed to be equally effective. Interestingly, as with Rovsing, gangrene was among the wide range of conditions from senility to diabetes which he claimed to benefit.
In the early 1920's, a flamboyant Russian‑French surgeon called Serge Voronoff working in Algiers, made his fame and fortune by transplanting chimpanzee and baboon testicles into humans, and claimed they had powerful rejuvenating effects. This work naturally attracted great medical and public interest, and international deputation's of doctors as well as patients from many countries made the pilgrimage to Algiers to investigate his "monkey gland" treatment.
If Voronoff was just fooling people, he did so with a lot of detailed evidence and seemingly convincing results for at least a decade. Even my first professor of physiology at the Middlesex Hospital in London, Samson Wright described Voronoff’’s work in detail in his standard textbook of the day in 1926. "In successful cases it is claimed that very striking results are obtained from this operation. Old people, with marked signs of senility, are claimed to be thus transformed into vigorous energetic individuals. Previously castrated person's may regain their secondary sex character ‑ e.g. growth of beard and moustache may occur".
The same writer obviously took this work seriously because he went on to say "While Voronoff’’s operation appears quite justifiable in young subjects in whom the testes have been damaged or destroyed by injury or disease, the treatment of senility by this method is more questionable. We have no proof whatever that senility is solely due to atrophic changes in the testis; it is almost certain that many other factors are concerned. Though the testicular graft may stimulate physical activity and sexual desire, it cannot restore the worn heart, arteries and essential organs to their normal state. There is a grave danger that excessive strain may be put on damaged structures, with disastrous results".
These are the same lines of argument still used today by doctors urging the fatalistic "do‑nothing" option in relation to the possibility of hormone replacement treatment for men, saying "Its just your age ‑ What do you expect at fifty, sixty, seventy or whatever your age is?" Along with women who are experiencing the many benefits of HRT, the answer should be as with Dickens's "Oliver", a definite "More!". Something is going to fail at some time in one of our body's systems, but shouldn't we at least be looking at every reasonable option for staying as mentally and physically active as we can, for as long as possible? Yes, the benefits have to be weighed against costs and dangers, but doctors should be continually assessing the evidence for and against each treatment and offering it to the patients to decide for themselves, and not prejudging the issues.
As the war clouds cleared in Europe after the first World War, a great pharmacological arms race developed with three drug firms competing to be the first to produce the active ingredient of the testicles in pure chemical form. It is an amazing story of synchronicity that after a search for the essence of manhood lasting over four thousand years, the three different groups passed the finishing post within four months of each other.
First past the post on the 27th of May 1935, was Ernst Laqueur, a Professor of pharmacology in Amsterdam, who lead an excellent research team for the Organon drug company, and emerged triumphant with a few precious crystals from a veritable mountain of bulls testicles, and submitted a paper called "On crystalline male hormone from testicles" and coined the name testosterone for it.
Second was a formidable, dynamic German chemist with a duelling scar on his left cheek, Professor Adolf Butenandt. He was working for the Schering Company in Berlin, which had managed to survive the first World War with its manufacturing capacity intact, and in 1923 thanks to hyper-inflation made a profit of 286 million billion marks, after tax, giving the shareholders a dividend of two billion percent. Some of this profit it invested in collecting 25,000 litres of policemen's urine, enough to fill an Olympic size swimming pool. From this Butenandt with bravery clearly above and beyond the call of duty, extracted 15mg, a few crystals, of a relatively inactive urinary breakdown product of testosterone called androsterone.
He then decided that method of preparation was too much like hard work, and thought up the much more commercial way by which testosterone is made to this day. He methodically worked out its structure and then produced it, as does the body, from cholesterol, its natural precursor. He sent his paper on this process and the structure of testosterone itself to the German Journal of Physiological Chemistry on the 24th August 1935.
Just one week later a Swiss chemical journal received a paper from Leopold Ruzicka, a Jugoslavian chemist working for the Ciba company in Zurich, announcing a patent on the method of production of testosterone from cholesterol. For this work, he and Butenandt received the Nobel Prize in 1939.
Within two years of these momentous discoveries a variety of testosterone preparations were in clinical use. It had soon been found that because it was an oily substance which didn't dissolve readily in water, that in the pure form it couldn't be absorbed by mouth. A slow release form that could be given by injection, testosterone propionate, was one of the most widely used and proved very successful in patients whose testes were insufficiently active for a variety of reasons. Rather like insulin injections for diabetics which had been introduced fifteen years earlier, it was dramatically effective in restoring the two big V's in men's lives, Vitality and Virility. Now that you could 'get it in a bottle', testicular transplants and extracts went out of the window.
Studies on patients in the late thirties and throughout the thirties and forties showed a wide range of benefits in several serious medical conditions, ranging from heart and circulatory problems, including even gangrene, and diabetes.
Though the injections lasted about three days, another form of testosterone as compressed crystals fused together to form tablets and later small cylindrical pellets, which under local anaesthetic could be implanted under the skin of the buttock or abdomen was introduced. This was both effective and convenient, as the implant continued to act for six months. Sixty years later this is still one of the best methods of giving long term testosterone treatment. There are few medical preparations, particularly in endocrinology, which have stood the test of time so well.
A third type of preparation which was also made in the early years was a water soluble form called methyl testosterone. Unfortunately, though effective in relieving symptoms, this proved very toxic, especially to the liver. As it was so widely used for over fifty years, and was included in a wide range of under‑the‑counter, gold and silver covered pills, claiming almost magical powers in the sexual arena, it has done a great deal of harm to the safety image of testosterone in many doctors minds. It is amazing that it is still almost the only form of oral testosterone preparation to be available in the United States, when its dangers have so long been recognised, and it has been taken off the market throughout the rest of the World where several safe oral forms have been introduced.
Testosterone used to treat the Male Menopause
From 1940 onwards, largely because of the obvious improvements brought about by testosterone, it was generally accepted by many doctors that there was a group of symptoms commonly experienced by men in their fifties that were similar to the female menopause or climacteric, from the Greek word klimacter , meaning the rung of a ladder, and hence a critical period in life at which the vital force begins to decline.
An outstanding paper of this time, which used testosterone as definitive proof of the existence of the male menopause, was published in the prestigious Journal of the American Medical Association in 1944. It was called "The Male Climacteric, it's Symptomatology, Diagnosis and Treatment" and was by two American doctors, Carl G. Heller and Gordon B. Myers. It is well worth looking at this paper in detail, as the case has seldom if ever been better made.
The symptoms which they attributed to the male climacteric were exactly as described in the last chapter of this book, i.e. nervousness, depression, impaired memory, the inability to concentrate, easy fatiguability, insomnia, hot flushes, sweating, and loss of libido and potency. They began by listing all the points raised by those who were sceptical of the existence of this condition, and then used their clinical studies to answer them one by one.
The majority of these queries were based on the general view that no objective evidence had been put forward to prove it was an actual clinical entity, or to differentiate it from neurosis or impotence of purely emotional origin. Also many men remained fertile to an advanced age, and did not show the marked physical changes in body form that women showed in the days before HRT became common‑place.
To study these points, they developed a measure of testicular function based on the hormonal feedback mechanism which exists to control the production of testosterone by the testis in men, and oestrogen by the ovary in women. When the level of testosterone in the former or oestrogen in the latter drops, the small gland at the base of the brain which is in over‑all control, the pituitary releases more of two hormones, gonadotrophins, so‑called because they stimulate these sex‑glands. When the level of testosterone is adequate for the body's needs, the gonadotrophins fall to a low level. Now they can be measured by sensitive chemical tests on the blood, which can be used in the diagnosis and treatment of both the male and female menopause.
In those days they had to extract a twelve hour over‑night sample of each man's urine, inject the extract into immature female rats, and measure the increase in the weight of their ovaries caused by the gonadotrophins in the sample. This simple biological test gave surprisingly clear‑cut results. The urine of normal men, or those whose symptoms were due to anxiety or neurosis, showed virtually no gonadotrophin activity in the urine. Those whose symptoms were due to a true male‑climacteric syndrome showed high levels of urinary gonadotrophins, as demonstrated by the ovaries of the test rats doubling or trebling in size.
This carefully performed and detailed study gave unequivocal evidence that the male menopause was a physical fact, and not just a fiction created by the emotionally disturbed and neurotic. Also, when a therapeutic test was carried out on samples of both groups of men by giving injections of testosterone propionate, the neurotic group "experienced little, if any, improvement in potency or in well‑being".
By contrast, in the male menopause group "Definite improvement in the Symptomatology was noted by the end of the second week in all of the twenty cases treated. Complete abolition of all vasomotor, psychic, constitutional and urinary symptoms was accomplished by the end of the third week in 17 of the 20 cases treated. In the remaining three cases vasomotor and urinary symptoms were abolished but the psychic and constitutional symptoms persisted in spite of continuation of treatment for several months and doubling the dosage for brief periods. It was concluded that these three persons were suffering from involutional melancholia "(depression of old age).
The same study also answered a frequent criticism of testosterone treatment to this day, that it will restore libido but not help problems with erections, leaving the patient more frustrated than before. Heller and Myers experience coincides with my own when they stated "Sexual potency was restored to normal with these doses in all but 2 cases, in one of which involutional melancholia was present." They go on to remark that with increased dosage, "sexual vigour in both previously refractory cases exceeded that of normal men".
They further gave evidence that this is a real response to testosterone treatment and not just a placebo effect. "In 14 cases therapy was subsequently withheld for from four to fourteen weeks and in all instances the symptoms returned and sexual potency was again lost. On resumption of the therapy with testosterone propionate, relief of symptoms was again afforded and sexual potency returned. Thus the specificity of therapy was established.
To investigate further the possibility that the improvement may have been due to suggestion, placebo injections were administered. Ampoules containing 1cc of sesame oil, packaged similarly to the original testosterone propionate, were substituted without the patients knowledge in several cases. No improvement was noted in any case."
As well as recommending pellet implants for long term treatment, they made two final important points in this historic paper. These were that "the male climacteric is not confined to middle and old age but may occur as early as the third decade", and they concluded that, "whereas in the female the menopause is an invariable and physiologic accompaniment of the ageing process, in the male the climacteric is an infrequent and pathologic accompaniment of the ageing process". We will see later why the male menopause may have become more common half a century on and yet is still not being properly diagnosed or treated.
Starting in 1950, a German physician who trained in Berlin, Edinburgh and Glasgow, but set up in private practice in London's Harley street, used testosterone pellet implants to treat men in their 40's, 50's, 60's and 70's suffering what he called IDUT syndrome. These initials indicated the main features of the condition which were Impotence, Depression, Urinary disturbances and Thyroid over activity, and he attributed all these to testosterone deficiency. Included in the latter term were irritability, headaches and attacks of rapid heart beats, particularly at nights, which just about completes the classic picture of the male menopause.
Over twenty years he treated about 500 patients with very good clinical results. These he wrote up in considerable detail in five eloquent articles, and carefully documented the improvements in each symptom on his own rating scale. He also wrote a monograph describing his method of implanting testosterone pellets into the buttocks for Organon, the company who made the implants, and this is the method and materials that I use to this day.
Having spoken to his medical colleagues, several of his patients, and his widow Nancy Reiter, an interesting picture emerges of this remarkable man. He was a dynamic, charismatic individual who delighted in the improvements he saw in his patients condition. He too believed in a broad approach to treatment, and would sometimes take his patients to his favourite fish restaurant to teach them at a pleasant practical level of the benefits to virility of eating oysters, because of their high zinc content.
As Nancy put it, he was regarded with "plenty of scepticism from the Medical World ‑ But the patients kept coming!" A prophet unrecognised in Britain, he was well received in America where he published articles in the Journal of the American Geriatrics Society in 1963, 1964 and 1965, and in the latter year lectured at their 22nd Annual Meeting in New York City, receiving considerable interest and approval. In Britain he could still not get his message across, and so he devised a "cunning plan".
He went to a meeting on endocrinology at the prestigious "Royal Society of Medicine", the heart of the medical establishment, in Wimpole street in London, and stood up at question time at the end, to give a long fiery diatribe about the virtues of testosterone treatment. When the chairman of the meeting finally managed to shut him up, which took some doing because he was doing a very determined filibuster, he went to the front entrance of that august Society's imposing building, and met a group of journalists he had previously summoned. He then gave them full details of his learned address to the Royal Society, which was duly printed together with his picture in the newspaper that evening.
Perhaps not surprisingly, such direct action did not endear him to academic doctors, but he died much loved by his patients in 1972, truly another hero of the hormonal revolution.
The Danish doctor Jens Moller was one of the great pioneers of testosterone treatment. With all the fire and tenacity of his Viking ancestors he fought a thirty year war for its use against the medical establishment in Denmark and throughout Europe. I had the privilege of working with him during the last ten years of that war, and it was he who in 1977 first interested me in testosterone.
At the time I had been working as Senior Lecturer in Chemical Pathology at St. Mary's Hospital Medical School in London. Though my office and research laboratory were located within the Department of Professor Vivian James, one of the World's leading researchers on Steroid Biochemistry, which includes the study of testosterone, oestrogens, cortisol and other related hormones, I was more excited by the stress hormones such as adrenaline and noradrenaline which appeared more directly related to my theories on stress, tension and heart disease, my main area of research at the time.
However, I was very much interested in the benefits of exercise as a means of balancing up the effects of stress and a way of protecting the heart from its effects. As part of this programme of research, I was taking part in a study set up by the Medical Research Council at the City Gymnasium at Moorgate in London. The founder and owner of this gymnasium was an ex‑Olympic weight lifting coach called Alistair Murray, who with tremendous energy and enthusiasm originated the use of vigorous but not violent exercise in the form of circuit training in both the prevention and treatment of heart disease in London businessmen. We later wrote a book together called "F40 ‑ Fitness on Forty Minutes a Week" based on his ideas and reporting this research.
One day while I was at the gym he called me into his office to meet a tall Dane with what I thought was a tall story. Though friendly, this doctor had a military bearing and the charm of a diplomat which he could switch on or off at will, and when it was off he could be what he described as "very direct". In his seventies, though with the brisk manner and energy of a man twenty years younger, as I learned later he had a varied career which involved an amazing tale of how the subject of testosterone treatment could arouse extreme passions in the minds of medical men.
Born in North Jutland in 1904, he left home at the age of 16, and even without a university education, became a successful entrepreneur, working in turn in Paris, London and Berlin. Even with money to burn he found his business career meaningless, and at the end of World War II he enrolled at the University medical school in Copenhagen, getting his entry qualifications in three months rather than the usual year. He qualified five years later at the age of fifty, and began his medical career, which was to be as unusual and turbulent as his previous one in business.
After a variety of work in hospitals and the pharmaceutical industry, he decided he wanted to be a neurosurgeon and worked in Sweden for a time. As neurosurgical jobs were few and far between, he took a locum job with a private physician working in Copenhagen, a decision which was to alter the course of the rest of his career.
Doctor Tvedegaard, whose name I shall abbreviate to Dr. T for reasons soon to be explained, was already a controversial figure in Danish medicine because of his use of testosterone to treat severe arterial disease, particularly in the legs. He had studied the use of this hormone by German Doctors and seen amazing results even in the most severe cases with gangrene spreading from the toes to the rest of the leg especially in diabetic cases.
The typical history given by his patients was one of painful cramps in the calves of the legs on walking, especially uphill on cold days, a condition known as intermittent claudication. As the blood supply became worse this gradually progressed to more continuous pain even at rest, and in bed at night, so that the patient would have to hang his leg out of bed to ease the intense discomfort. Eventually the limb would stay cold and blue most of the time, and an otherwise trivial injury to the foot would turn into an infection leading to gangrene of one or more toes. According to conventional practice at the time, these would then have to be amputated, and the surgeons would start on what often turned out to be a series of amputations, nibbling their way up one or both legs to above the knee.
Testosterone injections, often in considerably higher doses than generally prescribed, seemed to have halted or in some cases even reversed the otherwise inexorable process at almost any stage. Walking distances would be prolonged because the cramps in the calves would come on later and later, and even disappear, leaving a very happy wanderer. Night cramps would also go, which greatly improved the quality of sleep. Cold, blue painful feet and legs would become pink and comfortable as the circulation mysteriously improved.
Even gangrene would heal without surgical intervention, much to the relief and delight of the patient's and their relatives. Though this did not necessarily prolong their lives indefinitely, it did give them a much better quality of life and could prevent them becoming crippled by their circulatory problems. Many was the patient who went happier to their graves with two whole legs rather than one or none as a result of this testosterone treatment.
Now this was very strange, and at the time inexplicable. However, even more curious was that instead of other doctors becoming interested in this treatment, investigating it further in an open‑minded spirit of scientific enquiry, and perhaps even trying it on some of their more severe cases, who had nothing to loose except their legs, the reverse occurred. Because testosterone treatment did not fit the medical orthodoxy of the time, was not recognised in the groves of academia, and was a dirty foreign product originating in still deeply detested Germany of all places, Danish doctors closed ranks and minds against it.
It seemed that the rigid, doctrinal, Galenic attitude had once again triumphed over the investigative, clinical, Hippocratic one. Though burning at the stake, other than intellectually, had rather gone out of fashion, doctors had other ways of dealing with troublesome medical heretics. Suppressing their ideas by turning down their papers for medical meetings and publications is a good start. Dr. T wrote three papers for Danish medical journals, but they were rejected. If the theories are not published or discussed they cant be any good can they? This is the cold‑shoulder, ignore them and they'll go away attitude which often works, but not in this case.
Dr. T was often outspoken and critical of his colleagues attitude and made many enemies among them. More drastic action was needed and an opportunity for discrediting Dr. Tvedegaard presented itself and was eagerly seized. In Denmark at that time the law relating to medicines said that conditions could be only be treated with the drugs officially recognised as being effective in those disorders. Because of prevailing medical opinion, not only in Denmark but in most other countries as well, testosterone was not on the list of drugs to be used for circulatory problems. Even if an army of a thousand people whose limbs had been saved marched up and down outside the Danish Parliament for a week, the law was the law, and medical opinion could not be moved to change it for sweet reason's sake.
Worse still, patients could have some of the costs of certain "vital medicines" refunded provided the condition for which they were given were on the authorised list, and the prescriptions were written on the appropriate red forms. Dr. T's deeply held view was that testosterone was a literally life‑saving "vital medicine" and because it came mainly from the testes, found a category of "genital insufficiency" which he thought qualified its use in the cases he saw.
Unfortunately this came to the notice of the Danish Health Service officials who reacted in a surprisingly dramatic fashion one day in August 1957. Rather than take the case up through the usual medical disciplinary channels, they sent the State Police round the same day to officially charge Dr. T and Dr. Moller that because testosterone was not a "Vital Medicine" they were betraying the Government for money.
This rapidly escalated into a very public "cause celebre" with many court hearings, and questions were asked in the Danish Parliament. Dr. T's health soon deteriorated under the strain, so Dr. Moller who was made of sterner stuff as you may have gathered by now, was left holding the testosterone baby.
Undeterred by rulings against them in the courts, he mobilised public opinion in their favour. He did a detailed study of the literature and went to Germany to discuss the use of testosterone with the leading endocrinologists of the day, who were very supportive of these ideas. He then organised a public meeting of over fifteen hundred patients and relatives to raise funds for the fight. He lined up doctors from the health authority in the front row, deluged them with this new scientific evidence and then said "contradict me if you can". They couldn't, and left the hall in a state of confusion and acute embarrassment.
The fight then got very dirty, and the police tried to seize all the patients case notes and deprive the defendants of their evidence. Dr. Moller took the case notes home and piled them in the fireplace, telling his wife to set fire to them if the police called while he was out. The prosecution even made up stories from patients about they way they had been treated, who when they found out totally denied them. Fortunately, they had many grateful and influential patients who kept up the legal battle on his behalf as literally their lives and limbs depended on it.
Eventually a Minister of Justice who was on the State Medical Ethics Committee, and had a close relative who was greatly helped by Dr. Moller's treatment, got the court's decision reversed and the case called off after a battle which had lasted two years. Not only that, but the Director of the Danish Health Authority, who had been one of Dr. Moller's fiercest opponents, saw the effects of the treatment on his family and friends, and changed to the extent that he became Director of LBK, the organisation which was set up to promote the use of testosterone. The facts in this amazing case are documented in a book called "The Tvedegaard‑Moller Trial: A Fight Against Injustice" written a year later by another Danish doctor who had supported their cause.
Though the medical establishment in Denmark generally remained hostile to the "Dr. Tvedegaard Treatment", which they used to tell their students was "Hormonal Humbug", Dr. Mollers practice flourished. He used to see fifty or more patients a day, who sometimes had to queue in the street outside his clinic in the fashionable Store Kongensgade (Great King Street).
As is traditional with native prophets, he began to receive much more recognition from the many distinguished doctors from America, Britain and all over Europe who came to visit his clinic than he did from those in Denmark who seldom came to call except when they wanted research funds from his rapidly growing charitable foundations. Not unnaturally these experiences left Dr. Moller feeling somewhat paranoid, and it became his mission for the rest of his life to hammer home the message of the effectiveness and safety of testosterone.
To this end he established the "European Organisation for the Control of Circulatory Diseases" or EOCCD, at a meeting of the European Parliament in Strasbourg in 1976, and enlisted many prominent politicians as well as doctors in his fight against what he called "The international enemy" of these disorders. From 1977 onwards I made many visits to his clinic in Copenhagen and saw for myself the dramatic benefits of testosterone treatment to the circulation, especially in the legs. I came to realise how testosterone had its effects, and helped Dr. Moller to edit the books he was writing into acceptable English.
Also I went with him as he charged round Europe in his capacity of President of the EOCCD holding meetings in London, Luxembourg, Strasbourg, Bonn, Berlin and Munich. We visited many eminent authorities throughout Europe, and he achieved a great deal of scientific support for his ideas. It was difficult to keep up with him even when he entered his eighties, and it soon became apparent that he certainly took his own medicine, which was as effective for him as it was his patients.
When he finally died in 1989, active to the last, he left thriving national and international organisations which are carrying on his work under the direction of his able young successor, Dr. Michael Hansen. This seems a fitting guarantee that Dr. Jens Moller's heroic work in the service of testosterone will continue to bear fruit.
This brings the testosterone story almost up to the present day. My own experiences in trying to prove the existence of the "Male Menopause" have closely mirrored those of many of the characters featured in this story, particularly Paul de Kruif, Dr Tiberius Reiter and Dr Jens Moller. Attempts to debate the condition and its treatment with other doctors, especially those in related specialities such as endocrinology and urology, have met more with what could best be described as blatantly illogical denial. This has been laced with emotion and rhetoric far exceeding the spirit of detached scientific debate. Interestingly, the broad minded family doctors with whom I have had the opportunity of discussing the subject individually, and in teaching seminars have been much more interested and open-minded in their responses, than the specialists.
It seems that history is likely to repeat itself, as it often does, and that Testosterone Replacement Therapy for men will arrive by the same route as Oestrogen Replacement Therapy for women in treating and preventing the miseries of the menopause. It was the enthusiasm of the women themselves experiencing the benefits of the treatment as received from the few medical pioneers first brave enough to prescribe it, which gathered converts to the cause. After several years of intense opposition, and predictions of doom and disaster from the majority of gynaecologists, doctors were carried kicking and screaming into the field. The situation has now changed to the point where the majority are in favour, and a few have become evangelical about, while still remaining generally hostile to the idea of providing similar treatment to men. A recent poll in a major British national newspaper established that 97% of its readers believed that the male menopause was a fact and should be treated. However, in the same month at a meeting of urological specialists at St. Bartholomew's Hospital in London, only one third agreed the condition existed, and even fewer considered treatment might be safe or effective.
Let's look at the experiences of some of the thousand or so patients I have seen over the last twenty years who have experienced symptoms they put down to the male menopause so that you can better make up your own mind on whether this is a fictitious condition, or one which is real and should be treated.