Chapter Six - Testosterone Replacement Therapy (TRT)

As will be emphasised in the concluding chapter, TRT is one of the broad range of methods for preventing and treating the male menopause.  Often however it proves the key to the door to recovery, and puts men in a more positive frame of mind to undertake the other necessary steps such as managing stress better, drinking less, losing weight and exercising which they know would help them, but lack the energy or willpower to do.

Before deciding whether TRT is suitable, and what additional treatments are needed to maximise its effects, the physician prescribing it will need to undertake a detailed "work-up".

When you go to him, your health history will should be taken carefully and fully, particularly seeking factors which might have damaged the testes or stopped them functioning properly, such as non-descent, inflammations or orchitis such as mumps, vasectomy and other traumas, and local anatomical abnormalities.                                            

Then there needs to be an "Andropause Check List" similar to the one given in the second chapter.  This will establish whether you have the symptoms which could be attributed to the andropause and how severe they are, as well as giving a baseline against which the effects of treatment can be measured.

Next comes a life-style and stress assessment  questionnaire, which can now be computerised to make it easier to apply and to analyse.  One version which I have devised and used for over ten years is called HEALTHCHECK.  Using as far as possible established and generally accepted questionnaires which have been tried and tested in written form for many years, it assesses the health history, lifestyle factors such as alcohol intake, diet, exercise, relaxation, and smoking habits, and stress related factors.

It measure the amount of stress in your life by getting you to answer which of a list of stressful life events have happened in the last year or you are expecting to happen over the next year, and how much you were upset by them. It then assesses your anxiety or depression levels over the last month, and how Type-A or quick-fire, hard-driving, time, time and deadline conscious, as compared to more easy-going, relaxed, laid-back Type-B behaviour you show.                                                         

Finally it does an "Energy Balance Sheet", looking at your energy income in terms of satisfactions in different areas of your life, including work, finances, friends, family and relationships, and then the energy drains such as tiredness, health worries, lack of control, down moods and bad habits.  It then instantly analyses the results and gives a detailed print-out of all the good and bad points in an easy to understand report.

Next comes a physical check with special emphasis on the heart and arteries, testicles, penis and of course digital rectal examination of the prostate gland.   For those over fifty, it is advisable to have a Transrectal Ulltrasound examination of the prostate, in addition to the mandatory Prostate Specific Antigen (PSA) blood test which is the best overall early warning system to exclude prostate cancer, and is essential before considering treatment with testosterone. Newer advances in PSA testing, measuring total and free forms of PSA may make the ultrasound examination, which is quite expensive and seldom popular, necessary less often.

Though the case for early detection of prostate cancer is still being fiercely debated by the for and against early treatment lobbies, five cases of early non-invasive prostate cancer were found prior to testosterone treatment in my first thousand patients, and only one developed it during treatment in my first thousand cases, and was picked up by the six-monthly repeat screens at an early, treatable stage.  In both cases this is a lower incidence than would be expected in a group of men the majority of which are over fifty, and would suggest that, by providing the benefit of this careful repeated screening, testosterone treatment is overall more likely to save lives from prostate cancer than to cause it.                                                                     

Finally, a detailed fasting blood profile including a hormone profile, full biochemistry with checks on the liver, kidneys, blood fats and sugar, and haematological measurements of the red and white cells, is carried out in the laboratory.  The hormone measurements include the total testosterone, and the protein in the blood which limits its action, Sex Hormone Binding Globulin (SHBG), from which the active fraction, the Free Androgen Index (FAI) can be calculated by dividing the first by the second and multiplying by a hundred to give a percentage.  This key factor should normally be in the range 70 to 100 per cent, and andropausal symptoms are almost always present when it falls below 50%. 

For reasons mentioned in Chapter Four on causes of the Andropause, while the total testosterone level is often normal, even if in the lower part of the range, the FAI is usually significantly reduced before treatment, and is the most reliable hormonal marker of the andropause.  No assessment of a man with symptoms which might be related to the andropause is complete without it.  However, time after time in my practice, men tell me "My doctor says it can't be anything to do with my hormones because he measured my testosterone and said it was normal".  Nearly always this means that, as in 75% of my patients, the total testosterone level was normal, but the SHBG had not been measured, or the crucial FAI calculated.  You have to delve more deeply into this complicated hormonal clockwork to get the diagnosis.

Also measured in the hormone profile are the two pituitary gland hormones which stimulate the testes, the Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH).  For the reasons again described in Chapter Four, the former, against textbook theory, is usually raised more than the latter in many, but not all, cases of the andropause.

Another important hormone which should be included on the initial screen is one from the pituitary gland, prolactin, which as its name suggests in women stimulates breast milk production.  It also acts as a natural contraceptive, reducing fertility while women are breast feeding, and helping to space out pregnancies.  It may be raised in both sexes during periods of stress,  which reduces fertility, and can lower testosterone production in the male.

Rarely, there is a benign tumour of the pituitary called a prolactinoma, which produces large amounts of this hormone, and testosterone levels fall dramatically.  This results in loss of libido and potency, and all the other signs of testosterone deficiency.  One positive benefit of the detailed hormonal profiling carried out in all cases before starting testosterone treatment, was that these tumours are detected at an early stage, before other side effects of the pituitary enlargement such as headaches and impaired vision due to pressure on the optic nerves are felt.  Fortunately,  in the five cases seen in my first thousand patients, their symptoms were dramatically relieved by an anti-prolactin drug called bromocriptin, which also shrank the enlarged pituitary gland back to a normal size and avoided neurosurgery.

One of the oestrogen group of hormones, oestradiol (E2), is also included and sometimes gives interesting information.  Since it is produced in men mainly by the metabolism of testosterone, where that is in short supply the E2 often goes down.  When the patient is overweight, there is a tendency for more of the natural testosterone, and even that given as treatment, to be converted to E2, and this may then rise to a level where it causes breast enlargement and may even reduce the action of the parent hormone.   This paradoxical reaction for unknown reasons only seems to happen in a few patients.  It can be reduced by a variety of changes in the treatment given, as some forms of testosterone are not converted to E2.  I am currently investigating the use of the newer forms of anti-oestrogen drugs, which are proving very effective in the treatment of breast cancer in women, and show promise as an additional weapon in  the treatment of andropausal men.

Unfortunately, as yet there is no convenient blood test for the oestrogen mimics, Xeno-oestrogens, or the anti-androgens discussed in Chapter Four, which may be playing a part in bringing on the andropause, and this would be a great boon to mankind, both in relation to this condition and falling sperm counts.

When the results of all these tests are in, which can usually be done within a day if you are eager to get started, then a second session is needed with your doctor.   At this you go over the results together, and draw up an overall treatment programme, which is usually not just giving testosterone, but also involves active input on your part, modifying your life style in a variety of ways, reducing weight and alcohol intake, moving to boxer shorts, and adopting stress coping strategies if necessary. 

Always remember, you are in the pilot's seat and in overall control of your life.  In relation to testosterone treatment, having had the risks and likely benefits explained and your questions clearly answered, you have to decide whether to have the treatment and literally, call the shots.

TRT can be given in the form of injections, pills, pellets and patches.  The decision who to treat, with which preparation in what doses , and for how long, must rest with the individual physician, as part of a joint and informed venture with the patient.  Here I can only give my personal experience, and views derived from that and a review of the extensive literature on the subject.

Though when asked where these testosterone preparations come from, doctors sometimes tell patients that it is extracted from Peruvian Bull's testicles in the mating season, both to explain the cost of the treatment and maximise the placebo effect,  that's a lot of "Bull" really. In actual fact it is made synthetically in a large scale drug manufacturing process, from cholesterol  the same raw material as the body uses to produce it.  The cost of these preparations at present is usually roughly two to three times that of equivalent oestrogen preparations used for female HRT, but hopefully as TRT is used more often, drug companies will be able to reduce this sex hormone discrimination against men.

When testosterone was first produced back in 1935 it was realised that being poorly absorbed and rapidly broken down in the liver, it would not be effective when taken by mouth.  The answer was to find different routes of administration so as to bye-pass the liver and chemically modify the molecule to slow its rate of absorption and breakdown.   One of the most effective means of doing this was to attach side chains to the testosterone molecule and form compounds called esters, the longer the side chain in general, the slower the rate of breakdown.

Injections

Injections of pure testosterone were tried early on, but were found to work for only two hours, and though the effects were nice while they lasted, some means had to be found of getting a longer period of action if the treatment was to become popular. The first attempt at this was by making an ester called testosterone propionate.  Having a short side-chain it only lasted  two or three days, but this enabled it to be used clinically even if it meant injections two or three times a week.  This was the preparation used in 1944 by Heller and Myers to demonstrate for once, if not for all, that the male menopause, or male climacteric as it was called then, is due to testosterone deficiency.  They also showed in a controlled trial using placebo injections of sesame oil, how the symptoms of this very real hormonal disorder, including erection problems, could be abolished by TRT.

After the Second World War research on finding newer and more effective preparations got under way, and an ester called testosterone enanthate (Primo-Teston Depot) was produced by the Schering company in Berlin and found to be clinically very effective.  Having a longer side chain, it was broken down even more slowly, and injections lasted two or three weeks.

It was this preparation which Dr. Jens Moller, who first interested me in this treatment, used with such impressive results in his clinic in Copenhagen for over thirty years in treating circulatory disorders. It was given in high doses of 250mg weekly or even in severe cases twice-weekly, and as in the case of James  described in Chapter three, usually gave a dramatic relief of symptoms within a few days.

It is also the best injectable form widely available in the United States at present, and it produced excellent results in a "Hormonal Healthcare Centre" I set up in Hawaii.  The patients I saw there showed just the same symptoms as the ones coming for treatment to London, and it seems that the andropause can strike with equal force even in the "Paradise Islands".

There are other esters, and cocktail mixtures of esters such as the commonly used Sustenon, available but they seem to have no advantage over testosterone enanthate.  They all share the problem that they give a  peak of testosterone after a few hours, which is higher than needed and might have some harmful effects, for example on the liver, or the surplus can be converted to oestrogen, which is again undesirable.  The level then falls steadily over a week or two to a trough which may be insufficient to relieve the menopausal or circulatory symptoms.  The patient is aware of these ups and downs of the testosterone levels, and his life can be a roller-coaster ride of emotional and sexual highs and lows which most men, and their partners at home and in business, do not appreciate.   Also the injections, usually given into the buttock, are somewhat painful and quite expensive, which limit their availability and popularity especially for long-term use.

To overcome some of these disadvantages, several very promising new injections are now undergoing clinical trials, and offer the possibility of an extended action lasting between two and four months per shot. This would also get round the problems of poor and variable absorption of the oral forms, where 50 to 80% of this expensive hormone goes down the toilet, the problem of fluctuating blood levels, and the natural dislike of most men to taking medicine two or three times a day, perhaps for years on end.

Pills

It was a tragedy for testosterone treatment that the first oral form to be produced back in 1935 was methyl testosterone.  This is because it was effective but had some very dangerous side-effects which have tarnished the medical image of testosterone to this day.  Even though we now have much safer preparations, it can be obtained over the counter, without prescription, in many parts of the far East and this is still the only oral form of testosterone available in the United States.  Why is that watchdog of American Medicine,  the Federal Drug Administration (FDA), still asleep in allowing this drug on the market, while keeping the much better and safer varieties of this vital hormone out?

It's harmful side effects include a particularly bad effect on the liver, causing damage to the cells, resulting in cysts and even cancer, which is usually rare as a primary site.  Unlike other forms of testosterone which generally have a good effect, it sends up blood fat levels, particularly cholesterol. This is why one of the doctors who is a leading authority on testosterone, Professor Eberhard Neischlag from Munich, firmly stated in his 1990 review of different forms of testosterone treatment:  "Because of the side-effects methyl testosterone should no longer be used therapeutically, in particular since effective alternatives are available.  The German Endocrine Society declared methyl testosterone obsolete in 1981 and the German Federal Health Authority ruled that methyl testosterone should be withdrawn from the market in 1988.  In other countries, however, methyl testosterone is still in use, a practice which should be terminated." These are harsh words indeed, with which I entirely agree.

The dangers of this compound being foisted an a largely unsuspecting public were vividly brought home to me recently by the story of an engineer called Ken who had been forced to go overseas to get his testosterone supplies.

"At the tender age of thirty-seven I started to feel a severe lack of energy, and losing interest in everything, life just seemed too much bother.  My work as a service engineer involved new techniques using computers, and I started only just being able to keep up with the rapidly advancing technology, instead of being ahead of it as I had been before.  This, and my reduced libido and increasing difficulty with erections all combined to make me feel mildly depressed and generally flat.  Even my physique started to deteriorate, and when playing squash, or even carrying a heavy tool box up stairs, began to make me puff and pant.

After trying all sorts of things from hypnosis to acupuncture and herbal remedies for three years, I went to my family doctor, who checked me over.  After a blood test he said my testosterone was low normal, but said he didn't advise any treatment.  When I persisted, he got quite irritable, and said "Well, your work takes you round the World a lot - Why don't you get some on your travels?".

At the time I was spending alternate months in Thailand, so on my very next trip I went into a drug store over there, where you can get about anything over the counter with no questions asked, and got some "Metesto".  The label on the bottle said that each white tablet contained 25mg of Methyltestosterone, made in Bangkok, so it sounded like just what I needed.  The instructions were in Thai, so as there were a hundred tablets in the bottle and I wanted them to last a month, I decided that one three times a day would be the right dose, and away I went.

I must say, within a few days I began to feel much better, quite my old self.  My wife said I looked better when I got home at the end of the month, but the job finished and when the pills ran out, all the old symptoms came back.  This time I went to a specialist in the field, who after detailed tests said my testosterone was now only a tenth of what it should be, and the form of testosterone I'd taken had caused some hopefully temporary liver damage and raised my blood cholesterol.    He put me on a safer preparation also taken by mouth and within three months I was feeling fine again, and my liver function and cholesterol were back down to normal.

Now two years later I'm having pellet implants of testosterone, which keep me feeling very well and fit.  The funny thing is that my wife, who is going through the menopause and  couldn't keep up with my libido, which has returned to what it was before my problems started,  is having just a touch of testosterone in with her oestrogen pellet implants, so that we have ended up on the same medicine.

There are two much safer oral preparations available in Europe, South Africa, and Australia, and I have used them both extensively over the past seven years in treating over a thousand patients  with symptoms of the andropause.  The effectiveness of these treatments and the lack of adverse side effects are described later in this chapter.

The stronger of the two preparations is a long chain fatty acid ester called testosterone undecanoate, first used clinically about twenty years ago.  It is known under the trade names given to it by the Belgian company Organon that makes it, of Restandol in Europe, and Andriol in the rest of the world, including Canada where it has only recently come onto the market.

It is made in small oval reddish-brown oval capsules containing 40mg of the ester, equivalent to 25 mg of testosterone.  It is dissolved in arachis oil so that when taken after a meal it is absorbed by the fat droplets coming from the small intestine, goes into the lymphatic drainage, and bye-passes the liver so that it is not immediately broken down.  Peak serum levels are reached after two to four hours, and most is broken down by eight hours, so that this form needs to be taken two or ideally three times a day.

The other safe oral preparation is mesterolone (Pro-Viron), which comes in the form of white 25 mg tablets made by the German firm of Schering.  Unlike testosterone itself, and other testosterone derivatives, which are broken down to both an active product called dihyrotestosterone (DHT) and oestrogens, mesterolone only produces raised levels of the former, which makes it a weaker androgen, particularly in relation to improving both libido and potency.  However for unknown reasons, it still sometimes seems to work when the undecanoate fails, and so is a useful reserve form, especially when it is wished to maintain or even improve fertility, which the other preparations may suppress.  It can for example help young men with the "locker-room syndrome" mentioned earlier, and those who wish to have more facial and body hair to make them feel more "macho".  An example of this type of case is

Nick:

Though I'm twenty-two now, and managed to finish my course at university where all my friends claimed to have scored one or more times with girls, without quite managing it.  Since someone said my penis seemed rather small in the showers one day after a rugby match two years ago, it really seems to be shrinking.  This shattered my confidence and I stopped getting firm erections even when I masturbated..

I felt so bad about this that I gave up athletics and football, and became what you call a computer nerd, preferring the internet to basketball.  Though I took some drugs in my teens, I think it was more a very bad attack of glandular fever I had when I was fifteen that caused the trouble.  Because I was very worried about this I went to see a psychiatrist who tried some tranquillisers on me which didn't seem to help at all, and probably made the erection problem worse.  Then I saw a urologist, who took one look at me and said i was a perfectly normal size and should forget about it.

But as I couldn't, I went to see an andrologist who took a careful history, examined me fully and did a detailed hormone profile.  This showed a slight decrease in the free, active testosterone, perhaps due to the glandular fever or the stress of my final university exams, and he said that he would give me a short course of a mild form of testosterone called Pro-Viron to boost my confidence.

That was six months ago, and it seemed to give me a kick start and make me feel confident enough to start a relationship with a girl, with whom I'm having regular sex.  She really is very complimentary about my penis and it seems to respond very well to this, even though I've been off the Pro-Viron for three months now.

Pellets

Pellets made of crystals of pure testosterone fused together under pressure or by heat have been made by the Belgian company Organon and used clinically since 1937.  The safety and effectiveness of this preparation can be judged from the fact that it has been used virtually unchanged for nearly 60 years and has an excellent "track record".  Under a local anaesthetic, six to ten of the small cylindrical pellets, each containing 200mg of testosterone, are introduced though a single large needle deep into the fat of the buttock or lower abdominal wall.  Apart from the initial sting of the local anaesthetic it is a painless procedure taking about half an hour.  It gives good levels of testosterone for around six months, and is still the longest acting and most steadily effective form of TRT available.

Many patients enjoy the freedom from taking the testosterone undecanoate capsules on which they usually start, and feel, like the petrol advertisement, that it puts a "tiger in their tanks", for six months at a time.  It also gives the most sustained and natural pattern of testosterone related hormones, with no excessive rise in DHT.  The only occasional side effect is that one or more of the pellets tracks to the surface, and discharges itself, after which the puncture site heals over again.

One reason for believing that the very effective relief of andropausal symptoms is not a placebo reaction, is not only that it goes on working for year after year, but that even when he does not know what to expect, the patient experiences a gradual return of symptoms which is obvious both to himself and his family every six months or so.  This is often reported as "My battery is running down and I need a top-up".

The long-term safety of correctly applied testosterone treatment in general, and this method in particular, has been clearly demonstrated by over a hundred patients attending my clinic who have been kept free of andropausal symptoms by the implants for over five years now, especially two who have overall been treated for primary testicular failure since their teens with testosterone implants for twenty-five and fifty years respectively.  The later was one of the first patients in Britain to be treated by this method, and Ben’s story is part of its history.

“When I was a young boy, only twelve in fact, my father spotted that my testicles were not in the usual place, having stayed up in my abdomen.  This was very worrying to me and my parents who though I was never destined to go through puberty or become a proper man because I was suffering the then untreatable condition of what was called "Primary Hypogonadism".

Then at the age of seventeen, with no sign of a breaking voice or body hair like the other boys in my class at school, I had a lucky break by being referred to a Dr Peter Bishop, who was Professor of Endocrinology at Guys Hospital in London.  He had just been over to the United States and learned of a technique of implanting pellets of pure crystalline testosterone which they were using over there.

From 1944 onwards I started having the implants every six months into the side of my thighs, which was where they did them then.  I got to know the clinic staff very well over the years, and they shared my pleasure in going through a normal, though somewhat late puberty, getting a job in the civil service, and then getting married at the age of twenty-four.  I had a happy, sexually active married life, but with no children of course as the undescended testicles never worked, and had to be removed when I was twenty-six to prevent them developing cancer.

 At the end of every six months, I could feel the effects of the testosterone beginning to wear off.  At about the same time I started to feel tired, my interest in making love to my wife would die away, and it became too much like hard work.  The most severe of these withdrawal symptoms though were violent headaches, like bad migraine.  Also my penis seems to shrink in, and my confidence just goes.  Within a fortnight of each implant I felt like Chris

Its true I had a prolonged adolescence, which seemed to go on till middle age, but I never expected it to merge straight into what seemed suspiciously like a "Male Menopause".  What a young lad again, and generally more "cock-sure" in every sense of the term.  Girls looked nicer, my beard growth speeded up, my blood felt hotter and I seemed to glow with health.

Imagine my surprise and distress then when after being on the implants for over forty-seven years, I got a letter from the consultant who had taken over running the clinic to say that because of  "extreme cash pressures" they would no longer be providing an implant service, and we would have to go to our family doctors to get injections every two or three weeks.  Sometimes when I'd missed an appointment at the clinic, I'd had to try these injections for a month or two, and like the couple of hundred other regulars at the clinic I knew these injections were not nearly as good or as convenient, and certainly didn't give anything like the  same steady reliable benefits as the implants.  It seemed a rather cynical move on some administrators part to shift the expense of our testosterone treatment off the hospital budget into that of family doctors round the country.

Then I had my second lucky break, and found a private doctor who was using the good old fashioned pellet system and everything is fine again now.  I've been having the implants for another five years, taking me over the half century of implants mark. This must say something about the safety of testosterone treatment as my six monthly blood checks show my body chemistry is fine, especially the prostate test which is as low as that of a thirty year old.

Though I've retired now, I feel very fit, and have taken up growing moustaches of different styles, which I think make me look rather distinguished really.  Certainly my wife must be very tickled by them, as we had sex five times last week, which is not bad for a nearly seventy year old who got off to a slow start in this area of his life.

Patches

Different nationalities seem to have different favoured routes for taking medicines.  The British are given grace to persevere with their oral tradition, and have a pill for every ill.  The American's are more impatient and direct, preferring injections, and have a shot for every spot.  The French are a more sensuous race, favouring suppositories and creams, and find a pessary very necessary and that a balm can make you calm.  So it was naturally a French doctor, Dr. Jayle who as long ago as 1942 prepared a cream containing testosterone, and it became quite popular, with French men at least, who claimed it did wonders for their amour propre.  French women were not so enamoured with this treatment because they found that the cream rubbed off onto them, and while it enhanced desire, it put hair on their chest and face, as reported by another French doctor, Dr Delanoe in 1984.

Undeterred, the French went on to develop a gel called Andractim containing one of the active derivatives of testosterone, dihydrotestosterone (DHT), which they assured the ladies was quite safe because it was rapidly absorbed even when rubbed over a large area of manly chest twice a day.To make doubly sure however, they recommended controlling passion for ten minutes after application of the gel, and then having a shower to wash off any excess.  We must just hope that they read and obey the writing on the tube every time, because men usually need a large dose of testosterone to improve andropausal symptoms, while in women a little goes a long way.  Also DHT alone, while promoting facial and body hair growth, as seen with mesterolone treatment which trebles DHT levels, has generally less effect on libido or erection problems in most cases than the pellet implant which leaves DHT levels unchanged.

The big breakthrough in patches came with the development by an American, Dr.Virgil Place, working for the ALZA Corporation in Palo Alto, California.  He developed a whole series of Transdermal Therapeutic Systems (TTS), including the HRT patch for women, called Estraderm. As he told me once, he had "a heck of a job" getting the female patch accepted.  It was rather like the incredulity that Sir Walter Raleigh met with when he returned from America with a new drug delivery system consisting of the leaves of a plant which you dried, rolled up, and then set fire to before you inhaled the smoke.  However, like that system, once it was marketed properly, it soon became a multi-million pound industry World-wide, but unlike smoking, is a much healthier habit giving benefit to millions of menopausal women.

As Dr Place explained however, developing the male patch and getting it accepted gave even greater problems.  Firstly, a much larger dose of testosterone has to be delivered in the hormone deficient male than the minute amount of oestrogen needed in the menopausal female.  Secondly, the only area of skin thin enough for the testosterone to get through was thought to be the scrotum, and there the skin was hairy and so sensitive that you couldn't use adhesives, which are irritant, to stick them on.  So he came up with a patch called Testoderm, which was applied in the morning to the shaved scrotum, itself a ticklish business, and was renewed each day.  This appliance of science became known as the "Bals-Pratsch Patch", named after Dr. Monica Bals-Pratsch of Munich University who was the first to report in 1986 a clinically successful trial using the system.

However, extensive trials of the system showed that it was inconvenient to use, likely to be expensive long-term, and had the theoretical disadvantage of producing an abnormal hormone profile.  This was because the scrotal skin happened to be the only area of the body rich in an enzyme called 5-alpha reductase which converted the testosterone to DHT while it was being absorbed.  For all these reasons, Testoderm was never marketed on a commercial basis, and has now been superseded by a patch with an even more efficient delivery system which can be applied to any area of skin, even like the female HRT patch, to the buttock.

"Androderm", as the new patch is called, was developed by an American company called Theratech Inc., and is being marketed worldwide by SmithKline Beecham. This is a very promising development, and has undergone multicentre controlled clinical trials showing its safety and efficacy in studies at Johns Hopkins University, the University of Utah, and Karolinska Hospital in Stockholm, Sweden.  It was found that two patches applied every night for periods of up to a year restored a normal hormonal pattern to nearly a hundred "hypogonadal"  aged 15 to 65.  The main side-effects were limited to slight skin irritation at the site of the patches, a common complication of the female HRT patch. With this excellent research data behind it, the patch received Federal Drug Administration marketing approval in America with a speed that surprised even the manufacturers, and has just been released in the UK as "Testopatch", causing renewed media interest in the whole subject of the andropause.

Here again controversy arises because to meet with orthodox medical approval the manufacturers have obtained a licence to market the new patch for the treatment of male "Hypogonadism", which is an elastic-sided term meaning many different things to many different doctors.  They might well take the view quoted in Lewis Carroll's "Through the Looking Glass" - "When I use a word" Humpty Dumpty said in a rather scornful tone, "It means just what I choose it to mean - neither more nor less".

The conventional medical definition would be where the total plasma testosterone is below the "normal range".  But we have seen, and the majority of andrologists would agree, that it is the free, biologically active, as represented by the "Free Androgen Index", which in actual fact determines the adequacy of testosterone for the body's needs.  Strict application of the former definition, as my research has shown, would exclude over 85 % of patients with clear-cut andropausal symptoms from the benefits of treatment with any testosterone preparation, including now the patch.

Also, there is no real agreement about what the so-called normal range actually is, particularly in men over the age of forty.  Professor Alex Vermeulen in the University of Ghent in Belgium has spent a large part of his long and distinguished career in trying to establish this very point.  He has found that that studies to establish plasma levels of the male hormones at different ages can get totally different results according to whether you include or exclude either sick, or exceptionally healthy men, particularly those over the age of sixty, and this does not include the effects on the levels of tissue testosterone and DHT which are more than halved.  How do you establish a normal range to diagnose a condition, when fifty, sixty or seventy percent or more may be suffering some related symptoms which could be helped by treatment?

Add to that the variation of testosterone levels as measured in the same sample in different laboratories using a wide variety of methods, often giving different results, and the textbook definition of "Hypogonadism" looses most of its meaning in the real clinical world.  The situation is made even worse by the fact that the units in which all the sex hormones are measured differ between America and Great Britain, together with the rest of Europe, two great nations divided by uncommon units, so that frequently doctors on one side of the Atlantic don't know what reference ranges the other side are using.

However, if the new patch can breakthrough the current terminology barrier limiting its use, it is likely to be a highly acceptable system and to some patients who find other routes of treatment unattractive represents a breakthrough in treatment of the andropause.  It will also be ideal for the type of double-blind controlled  trials which are thought to be necessary to prove that drugs are effective in a particular condition.  However already some men are reporting being alarmed to find that they wake up in the morning with their partners HRT patch sticking to them, it having rubbed off in the night and transferred itself.  Fortunately, as the makers say, its an unlikely accident, but how will the women feel when they wake up wearing a King-size male patch, and have to get up and shave?  Ah well, medicine is an imperfect science!

Results of TRT

The results of the study carried out on of the first 400 of now over 1,000 of my patients in London gives I think good evidence that the male menopause is a reality, due to either an absolute or relative deficiency of testosterone, which can be treated safely and effectively with TRT.

The age of the subjects ranged from 31-80, the mean being 54, which indicates the diverse range of often overlapping factors which can bring on the andropause.  This gives it a wider age span than the traditional 45-55 which covers the onset of the menopause in women.  Since the symptoms had on average been present for around four years however, the peak time of onset is identical.

The mental symptoms included fatigue in 82%, depression in 70%, and increased irritability in 60%.  The physical symptoms were aches, pains and stiffness, particularly in the hands and feet, in over 60%, night sweats in 50% and yet dryness and thinning of the skin in 46%.  Sexual problems were present in over 90%, and included loss of libido and erectile problems in around 80%.

For the reasons described in Chapter 3, in addition to the changes associated with ageing, possible overlapping causes of these symptoms were stress in 60%, alcohol in 45%, a wide variety of medicines known to affect potency or which might lower testosterone in over 30%, operations or injuries which might damage the testes or impair erection, especially in the 20% with vasectomy, another 30%, infections such as mumps, smoking, and obesity all at around 20% each.

Because of uncertainty about which form of testosterone might be most effective in relieving symptoms, and wishing to have a controlled comparison of the two treatment groups in this prospective study for research purposes, the patients were randomly allocated to medication with either mesterolone (MS) or testosterone undecanoate(TU).  Both groups also received advice on general measures such as relaxation, drinking less, weight loss, exercise and wearing loss fitting boxer shorts, and were followed-up with the same range of detailed blood tests, andropausal symptom check list and computerised psycho-social tests as in the initial "work-up" before treatment.

Depending on response and the patients wishes, after six months of either of the oral treatments, testosterone pellet implantation (TI) was offered as a choice for long-term treatment.

Clinically there was an over-all feeling of increased vitality and well-being in all groups.  Drive and assertiveness were observed to be increased by both the patients and their partners, but not to the point of aggression.  In fact many became happier, less irritable and generally easier to live with, and felt they were coping better at work and in their family lives.

Increased hair growth, particularly on the chest and pubic region was often noted by the patients.  There was no hair loss from the scalp, and many felt the condition of their hair and skin had improved, with a markedly enhanced ability to tan.  A few noted their hair colour had been restored.  Penile enlargement and increased genital sensitivity were also noted with satisfaction by some.

Unpleasant side effects were minimal, and limited to mild gastric irritation in a few patients on TU, and the occasional loss of one or more pellets when the implants were rejected, which is an infrequent complication of this otherwise very convenient and effective form of treatment.

Andropausal symptom scores all fell statistically significantly and total sexual activity, which includes both intercourse and masturbation increased in all three treatment groups.  The benefits were most marked in the implant group, particularly in terms of increasing sexual activity and improving the relationship with the partner.  Depression measures also decreased and went from being moderately severe back into the normal range.

On the safety side, blood pressures were unchanged or even fell slightly in the TU group after six months treatment.  There were no adverse changes in blood fat patterns, glucose, liver function tests, or any part of the detailed blood profile.  In particular, the early warning sign for prostate cancer, the Prostate Specific Antigen (PSA), did not change at repeated tests up to five years, there were no signs of enlargement of the prostate clinically, or on ultrasound scanning, and no tumours developed.

Though a degree of placebo effect cannot be excluded in this type of study, it would not seem to account for either the magnitude or duration of the benefits, or the hormone changes in the expected direction which accompanied them.  The very low test doses of either of the two oral testosterone derivatives given for the first month was effectively a form of placebo treatment to which the subjects usually failed to respond, when the placebo effect should have been strongest.  Only when the dose was doubled or trebled to therapeutic levels did they begin to feel the benefits.

Also with the implant treatment, it was only after two weeks, when the testosterone levels had risen, that the effects were experienced.  Similarly the observed benefits wore off and the symptoms, especially of fatigue, returned at around six months after the implant, when the hormone levels were dropping back towards their pre-treatment values.

Difficulties of double-blind trials.

George Bernard Shaw once remarked that doctors pour medicines, of which they know little, into patients, of which they know less.  In day to day clinical practice, the sum of knowledge is probably much the same, but the former is probably increasing, often at the expense of the latter.

Medicine has now become much more of a science than an art.  What once seemed simple is now complex.  Doctors used to give medicines and observe carefully what happened. If the patients seemed to improve they continued to use the treatment, and if they didn't, they stopped.  Hormone treatments such as cortisone, thyroid hormone and insulin were introduced in this way because the benefits were blindingly obvious to doctors and patients alike, and could make the difference between life and death.  In his use of testosterone in patients with severe arterial disease in the legs, Dr. Jens Moller saw the dramatic benefits of treatment in preventing amputation for gangrene in the same light as giving insulin to diabetics, and felt it would be unethical not to do so.

However, medical science, before it will accept any line of treatment as being proven, now demands what are known as "Double-blind Control Trials".  This means that the treatment on trial has to be given without either the patient or the doctor knowing whether active or placebo drug is being given at any one time.  Depending on the design of the study, whether it is cross-sectional, longitudinal, cross-over or the exotic "Latin-square", this can double, or even quadruple, the number of patients, the time needed, and often the cost as well.  It obviously limits the number of doctors who, without extensive and expensive research facilities, are able to undertake such studies, record and analyse them in the required statistical detail.

Also you now need to tell the patients that they are taking part in a trial, and for them to give informed consent.  This makes them dubious about the medicine, and in private practice patients want to be sure that the specialist they see is not acting "blindly", but giving them the best medicine he could choose for their particular case and that they are they are getting it straight away.  Where the medicine is effective in relieving their symptoms, in a double-blind trial the patients usually know before the doctor whether they are on the active drug or placebo.  There is also the confounding effect of the other range of life-style modifications which the doctor will recommend in some patients and not in others, and the variable placebo power of different doctors in encouraging the patients to undertake them.

The situation is even more difficult with testosterone treatments because, as was explained to me when I tried initially to get research funds,  many of the preparations have been around for between twenty and fifty years, so that they are not only out of patent protection, but in the case of pellet implants, out of the product license period.  This limits the interest of drug companies in such products, unless there is a new and difficult to reproduce drug delivery system involved, and they can see a large and guaranteed market.

Having said all this, some of the newer testosterone preparations such as the long-acting injections and patches may prove to be sufficiently "sexy" for the drug companies or medical research organisations to subsidise scientifically "pure" trials.  In the mean time we will probably have to present the relatively "impure" evidence of the practical experience of patients on treatment, combined with evidence from the literature and the type of cross-sectional research information on changes in symptoms and hormone levels reported in this chapter.

The data is there, carefully gathered over seven years in computerised format, testifying particularly to the safety and effectiveness of long term testosterone treatment, and I cordially invite my medical colleagues from an academic medical background to examine, analyse and report on what I regard as a gold-mine of interesting, important and exciting information.

Future Directions in Testosterone Treatment

It seems certain that testosterone is a hormone whose time has finally come, and that TRT  for men will take its rightful and very necessary place alongside HRT with oestrogen for women, as an integral part of preventive medicine in the Twenty‑first Century.  It is equally certain that new testosterone preparations will have to be introduced, as none of those presently available are ideal.

As an alternative to these treatments, it may be possible to stimulate the body's own natural production of testosterone, to slow its use and breakdown, or lessen the factors antagonising its action.  It may also be feasible to liberate and activate the testosterone already produced by the  body which would give a form of testosterone‑free testosterone treatment, an interesting therapeutic paradox.