Disclaimer: The views and opinions expressed in this article are those of the author and do not necessarily reflect those of Dr Grant Fourie.
The male menopause is called the andropause and androgen deficiency in the aging male is a very real phenomenon. It may be less sudden than the female menopause, but it is severe.
THE CAUSE OF ANDROPAUSE is decreased levels of bioavailable testosterone. Decreasing testosterone levels leads to increased aging of the heart and circulation, increased MI’s and CVA’s, decreased hemodynamic function, increased brain aging, decreased memory, increased dementia and Alzheimer’s disease, decreased cognitive function and cognitive impairment - even without dementia and loss of drive and competitive edge. Testosterone replacement can prevent these problems and significantly improve a patient’s quality of life. This paper will discuss the benefits of testosterone replacement on body composition, cardiovascular function, cognitive function and libido and sexual function. The potential risks of testosterone replacement therapy will be assessed, including the risks of prostate cancer and benign prostatic hyperplasia. Testosterone replacement for relative androgen deficiency in the female will also be addressed.
"We age because our hormones decline, our hormones don’t decline because we age."
Testosterone replacement therapy (TRT) is safe and it provides dramatic benefits. Testosterone decreases inflammation. Inflammation is a hot topic at present and chronic inflammation is linked to many diseases, including heart disease, cancer, and neurodegenerative diseases - one of the benefits of youthful hormone replacement is its anti-inflammatory effect. Testosterone also improves quality of life.
The general inflammatory state of low testosterone levels produces a general feeling of stiffness and pains in the muscles and joints. Fitness levels fall and workouts are not as effective as they used to be - if you don’t have the anabolic hormone to take that protein and put it in the muscle, it’s not going to work. Fatigue, depression, irritability, decreased libido, decreased erectile tension and increased refractory period between orgasms, are all symptoms of the male menopause - all of which lead to an impaired quality of life.
Is andropause a deficiency disease? The simple answer is yes. Korenman et al found that half of healthy men between the ages of 50 and 70 years have a bioavailable testosterone level below the lowest level seen in healthy men aged 20 to 40 years old. Thus, a normal 50 year old has a deficiency disease compared to a 20 year old. That is the rationale for replacing testosterone, not to normal-for-age levels, but to optimal levels.
Lab tests required for testosterone replacement therapy (TRT)
There are lab tests and there are patients. Lab tests do not always make sense. If all else fails, look at the patient. It is a controversial field. Yes, get labs tests. But, the patient counts more than the lab test results.The first test that needs to be done when considering TRT is total testosterone. Total testosterone is a measure of the testosterone floating around in the blood, a lot of it is stuck onto the sex hormone binding globulin (SHBG) and you cannot use it. The range goes from about 350 to 1030 nanograms per decilitre (ng/dl) in men and 10 to 55 ng/dl in women. It is important to check with the lab you use, as some use different units. Sometimes it is reported in nanomoles per litre (nMol/l). The conversion factor is 10.4 nMol/l=33 ng/dl. Remember, these are reference ranges. Normal ranges are not optimal ranges and you have to explain this to the patients when they see the results. It is a reference range. That is just statistics. It does not talk about optimal health. There is a circadian pattern to testosterone secretion, so draw blood for total testosterone in the morning.
Total testosterone may not correlate with bioavailable or free testosterone, depending on SHBG and albumin. SHBG holds on to sex steroids. It holds onto testosterone, tighter than oestrogen. Normal SHBG levels are 20 to 60 nMol/l in males and 40 to 120nMol/l in females. If this number is high or low is does not necessarily mean that something is wrong and that you have got to fix it, but it does explain things. Thyroid increases SHBG. We are treating a lot of patients with thyroid. Oestrogen and progesterone increase SHBG. Aging itself increases it. Testosterone, glucocorticoids, growth hormone and insulin decrease SHBG.
The reference range for free testosterone is in the region of 80 to 300 picograms per millilitre (pg/ml) for men and 1.1 to 6.3 pg/ml for women. Free testosterone is the fraction that is not stuck to SHBG or albumin. There are two main problems with free testosterone. Firstly, the portion stuck to albumin comes off and it is usable. Secondly, it is a difficult test to do and most doctors don’t ask the lab which method they used. The analogue ligand radioimmunoassay (RIA) technique is notoriously inaccurate. The research methods like equilibrium dialysis or ultracentrifugation are good, but are not usually done.
"The most useful test is the one for bioavailable testosterone. Bioavailable testosterone is a calculated number. The higher it is, the better."
The reference ranges for bioavailable testosterone are 120 to 600 ng/dl for men, and 2-20 ng/dl for women. Bioavailable testosterone is a measurement of the amount of free testosterone plus the testosterone loosely bound to albumin.
Dihydrotesterone (DHT), some people measure it, some do not. In the US, DHT is considered bad and is blamed for hair loss, BPH and even prostate cancer. However, across the pond in Europe, DHT is used often as androgen replacement. So, is it good or is it bad? Or do we just not know? Either way, the reference range is 30 to 85 ng/dl in men and 4 to 22 (ng/dl) in women. There is no need to routinely measure DHT.
It’s a different story with oestradiol. It is important to measure and control oestradiol levels in men. Men need oestradiol. You cannot let it drop to zero, but you cannot let it get high. This is what separates the men from the boys and the women from the girls in TRT. The reference range for oestradiol in men is 15 to 45 pg/ml; the optimal range is 15 to 25 pg/ml. Controlling oestradiol is the key. If you do not do that, you will be chasing your own tail.
Methods of TRT
When you think about TRT, it’s important to remember you are not just thinking about testosterone, you also have to consider DHT and oestradiol. You’ve got to remember that. Here are some of the options when it comes to TRT.Injections
One method of TRT is by giving injections of testosterone enanthate or testosterone cypionate. These are bio-identical because the ester hydrolysis that takes place in the blood, leaves you with bio-identical testosterone. In the past, patients were typically given 200mg every two to three weeks. It was a bad roller coaster ride as the patient got sky-high supraphysiological levels at the initial ejection, a lot of which was aromatised to oestradiol. And by the end of the two to three weeks, testosterone levels had plummeted to lower than baseline levels. However, if you shorten the interval to a weekly dose of 100 to 150mg, you’ve got a pretty smooth result and when given all the different options, most of my patients actually prefer giving themselves an IM shot once a week. It has to be given IM gluteal. Sometimes it hurts in the anterior thigh. The advantage of this method is that it gives you more physiologically stable levels and there is less aromatisation to oestradiol.
Oral
Oral TRT is not good. The FDA allows women to use methyltestosterone in Estratest, but does not allow men to get it. In fact, no one should be using it, as it is hepatotoxic. There is an oral form of testosterone undecanoate called Andriol that is not associated with hepatotoxicity, however this is not available in the United States. That is no great loss, as it does not work too well anyway.
Subcutaneous pellets
Another method of giving TRT is by using subcutaneous pellets. To implant the pellets, you simply need to give the patient a local anaesthetic and make a nick with a scalpel. Most of the pellets last for two or three months, but some last for up to six months. Pellets are good for people who are going travelling and don’t want to take needles or gels with them and for those who do not inject themselves. But the majority of patients think it is easier just to go ahead and give themselves the IM once a week.
Transdermal testosterone
The other main method of TRT is by using transdermal testosterone. Transdermal testosterone is available in the form of AndroGel or custom made from a compounding pharmacy. Transdermal testosterone is well absorbed in most men, but not everybody. Some patients just do not absorb transdermal testosterone in my experience. I don’t know why. I think AndroGel is the wrong strength because it is 1%, which is the female dose. It is better to get your transdermal testosterone from a compounding pharmacy because it is cheaper and you have complete control as you can make it any percent you want.
If you decide to go with transdermal testosterone there are a few precautions you need to tell your patients about. It is important to keep it off the scrotum if you do not like DHT. Warn patients about not getting the gel on women and children. It can increase hair growth in the area where you rub it in both men and women. Unfortunately, this is not the case on the head. It is also important to warn patients that free testosterone can actually decrease with transdermal testosterone.
Human chorionic gonadotropin
Through the miracle of biology, the alpha sub unit of human chorionic gonadotropin (hCG) is the same as the alpha subunit of luteinizing hormone (LH). This means that you can give men the female pregnancy hormone hCG, and if their Leydig cells still work (this technique works better in 40 to 50 year olds than 70 to 80 year olds), they will be instructed to make more testosterone. So, this is an option. One of the side effects of testosterone is a 10 to 15% decrease in testicle size. Men do not want that. So hCG is an option if it will still work. It is also a good option if they want to keep their sperm count up, as hCG has no effect on sperm count.
A typical dose of hCG is between 2000 to 5000 units per week, given subcutaneously. It is possible to use just hCG as TRT (you obviously need to monitor free testosterone to check that it is working) or you can cycle it with more traditional TRT every six months. Another alternative, is combining testosterone and hCG. This involves giving IM testosterone ester cypionate once a week, on day zero (0). On day 5 and 6, you will have a little bit of drop off and you can give a small dose (ie. 250 units) of hCG subcutaneous on those two days. If you go with this method, you maintain testicle size and you maintain sperm count.
If a patient has high levels of follicle stimulating hormone (FSH) and LH, then hCG is probably not going to work, because their body is already trying to tell the Leydig cells to make more testosterone and it is not happening. So, that gives you a clue as whether to use it or not.
Aromatase inhibitors
The best way to control oestrogen levels is to eliminate adipose tissue. Fat is a throbbing adipose organ that makes arachidonic acid and aromatase. So, adipose tissue makes oestrogen out of testosterone. That is not a good thing, so if a candidate for TRT needs to lose weight, you need to encourage them to do so. If you need to intervene pharmacologically, Arimidex works beautifully. The dose of Arimidex can be very small, 0.5mg two or three times a week, is often enough and that way you can optimise. What is the ideal oestrogen level? The ideal oestradiol level in men is approximately 20, but anywhere between 15 and 30 is good. You do not want to let it get over 50, because levels that high will start to cause oestrogenic side effects, such as tingling nipples and gynecomastia. On the other hand, you can’t let it drop to zero either. If it drops to zero, your patient will start losing bone. Therefore, it is a delicate balance, but it is easy to achieve.
Benefits associated with TRT
“Testosterone replacement improves libido, erections, cardiovascular status, body composition, cognitive function, mood, depression, glycaemic control and inflammation.”
There is a common misconception that testosterone is bad for the heart. However, the data shows exactly the opposite. The lower the free testosterone level is, the more likely a man is to have coronary artery disease. Testosterone replacement improves SD depression and dilates coronary arteries. Its effects upon lipids are variable, however, low testosterone is associated with a bad lipid profile. English et al found that low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina. While a study into the anti-ischemic effect of testosterone in men with coronary artery disease by Rosano et al led them to conclude: “Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease.” Bring on the IV testosterone. In fact, intracoronary testosterone has direct dilating effects on the coronary arteries. Thus, while a patch can be used, for testosterone to have a direct effect on coronary arteries, it has to be given intracoronary. Finally, Hak et al found that low levels of endogenous androgens increase the risk of atherosclerosis in elderly men.
"Therefore, the rumour that testosterone is bad for the heart, is clearly not true."
Why is testosterone good for the heart?
How does it work? Remember, the bad guy in anti-aging medicine is inflammation - chronic inflammation. Fish oil, low-dose aspirin, stress reduction, exercise and antioxidants, are good for health because they are all things that help to control inflammation. Testosterone prevents cytokine production, which turns on C-reactive protein, which turns on fibrinogen. Testosterone also prevents the formation of the adhesion molecules VCAM and ICAM, which cause the process of atherosclerosis. Thus, testosterone replacement is a very powerful anti-inflammatory treatment that can help to prevent atherosclerosis. Testosterone has also been shown to be of benefit in the treatment of chronic heart failure. Pugh et al found that testosterone increases cardiac output, decreases LV load and has no bad side effects.
A large review of testosterone replacement by Rhoden and Morgentaler was published in the New England Journal of Medicine in January 2004. Surprisingly, for a journal that is very conservative and is usually negative about controversial advances in medicine, the review is very positive about testosterone replacement. On the question of testosterone replacement and BPH, the authors conclude: “Multiple studies have failed to demonstrate exacerbation of voiding symptoms attributable to benign prostatic hyperplasia during testosterone supplementation.” Therefore, we can conclude that testosterone replacement does not make BPH worse.
What about prostate cancer? Here the authors concluded that there is “No compelling evidence at present to suggest that men with higher testosterone levels are at greater risk of prostate cancer or that treating men who have hypogonadism with exogenous androgens, increases this risk. In fact, it should be recognised that prostate cancer becomes more prevalent exactly at the time of a man’s life when testosterone levels decline.” Therefore, Rhoden and Morgentaler are basically saying that there is no clinical evidence that the risk of prostate cancer or BPH increases with testosterone replacement. In fact, it has been shown that the Gleason score, a measure of prostate cancer’s invasiveness and potential to metastasise, is inversely related to free testosterone levels. Cooper et al studied the effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen (PSA) levels in healthy young men. Participants were given testosterone intramuscularly at doses of 100, 250, or 500mg a week - 100mg per week is a reasonable dose for replacement, 250mg is too much (if you believe in physiological replacement) and 500mg is way too much for physiological replacement. At any rate, not surprisingly, serum testosterone increased and there was no change in prostate volume or serum and semen PSA.
"Morales and Prehn both concluded that there is no evidence to suggest that exogenous androgens promote the development of prostate cancer. Maybe we should think about something else - maybe it’s the oestrogens. Oestrogens and androgens are needed for promotion of prostate cancer and a combination of all the xenoestrogens that we are exposed to and the modern Western diet, may be what is promoting prostate cancer."
Testosterone is the major predictor of skeletal mass and it is synergistic with growth hormone (GH) and insulin-like growth factor-1 (IGF1). Testosterone can improve strength even without exercise, but there is a marked improvement if testosterone is taken in combination with exercise. There is evidence to suggest that declining testosterone may be responsible for frailty. And, frailty is a bad way to go. Sarcopenia, muscle weakness, osteoporosis, falling and breaking a hip - that is not a good path to go down. Declining testosterone levels are associated with accelerated osteoporosis, decreased muscle mass and anaemia. Replacing testosterone prevents frailty syndrome. Furthermore, testosterone counteracts cytokines. Cytokines trigger inflammation and inflammation contributes to frailty. That is why things like statins actually work against osteoporosis. It has nothing to do with cholesterol. Statins are anti-inflammatory. So, testosterone counteracts cytokines, counteracts glucocorticoids and counteracts the decomposition of our bodies and our minds with time.
What about insulin resistance?
Testosterone can be a very powerful tool for the control of insulin resistance. Replacement doses decrease insulin resistance, however supra-physiologic doses (ie. doses out of the youthful physiologic range), can make insulin resistance worse. Low levels of testosterone definitely play some role in the development of type II diabetes. Low testosterone is associated with syndrome X, hypertension, type II diabetes, fibromyalgia and coronary artery disease. Boyanov et al studied the effect of testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Subjects were given oral testosterone and the results showed that supplementary testosterone reduced haemoglobin A1c levels by 17.3%, led to a decrease in visceral obesity and improved symptoms of androgen deficiency including erectile dysfunction. Remember that visceral abdominal fat is a cytokine generating organ that produces inflammation.
Adverse effects of testosterone replacement
Does testosterone replacement increase prostate cancer risk or risk of benign prostatic hyperplasia? No, it does not. Are there any other side effects of testosterone replacement that need treatment? The only significant side effect that needs to be treated is increased red cell mass or polycythaemia. Oestrogen control may be needed if oestradiol gets too high. However, these potential risks can be kept minimal with comprehensive anti-aging medical care.
The major adverse effect of testosterone replacement is polycythaemia. Polycythaemia is more likely with injections than with gel. However, it is something that can easily be managed. Some people suggest that you should just stop testosterone replacement, however you can just do a phlebotomy or better yet tell your patient to donate blood if their haematocrit starts hitting around 55. Either way it is important to stay on top of this and certainly in the first few years of managing balanced hormone optimisation, it is advisable to test patient’s blood levels every three months. People with COPD, smokers and men with sleep apnoea, are at increased risk of developing polycythaemia. There has never been a case report of increased red cell mass causing a thromboembolic event. However, it still needs to be controlled.
Gynecomastia is a potential side effect of testosterone replacement thus it is important to monitor oestradiol levels and control them with aromatase inhibitors when needed. Fluid retention is rare. Does testosterone replacement accelerate male pattern hair loss? To be truthful, there is no data one way or another. Testosterone replacement can lead to a decrease in testicle size. With prolonged treatment, a decrease of 10% to 15% can be expected. Testosterone is a form of male birth control, because you’re suppressing FSH and LH, thus testosterone replacement does lead to a lower sperm count.
Testosterone replacement safety issues
A comprehensive evaluation of the patient is vital before prescribing a patient testosterone replacement. This should include a physical exam, a digital rectal exam, cardiac risk factors, fitness evaluation, bone density, body composition, cognitive function tests and laboratory tests - including all hormone levels, testosterone levels, free testosterone levels, PSA, sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and luteinizing hormone (LH).If a patient’s PSA is greater than four, or just seems higher than it should for the patient’s age, or there is abnormal digital rectal exam, or any other suspicion of prostate cancer, refer the patient to urology for evaluation and possible biopsy. If there is PSA velocity, thus meaning that the patient’s PSA levels has increased by more than 1.0 in a year, repeat the lab test, then, if velocity is still evident, refer the patient to urology. If PSA is greater than 4.0 and a biopsy is negative, testosterone replacement is okay. There is no need to withhold testosterone treatment once a negative biopsy result has been obtained. If the patient has had prostate cancer and has had a radical prostatectomy and two or three years their PSA is still at zero or at close to zero, then it is fine to go ahead with testosterone replacement. The risk might even be less than the average guy walking down the street.
Testosterone replacement in women
Women obviously need some testosterone. It is needed for sense of well-being, strength (especially upper body strength), nipple and clitoral sensitivity, body composition and bone density. Sometimes you get better results on bone density with TRT than with Fosamax, etc. DHEA can increase testosterone somewhat in women, but not in men. This is because DHEA in men is mostly testicular and in women it is half ovarian and half adrenal. If the ovaries are not making it, it is all coming from the adrenal gland. Thus, you can have relative androgen deficiency with normal levels in women.Women’s testosterone levels decrease by as much as 50% by the time they reach their 60’s. Furthermore, HRT, either bio-identical or old-fashioned Prempro, increases SHBG and decreases free testosterone. Symptoms of female androgen deficiency syndrome (FADS) include: impaired sexual function, loss of libido, energy loss, loss of well-being and depression. Thus, the symptoms of FADS are just like those of low testosterone in men. Testosterone deficiency is not just about sex in men and it is not just about sex in women either. Kaczmarek et al showed that decreased testosterone and free testosterone is associated with coronary artery disease in women, independent of other risk factors.
So just as in men, low testosterone, because of its anti-inflammatory effect, is associated with more coronary artery disease. Meanwhile, Dimitrakasis et al found that women given traditional HRT (hormone replacement therapy) plus TRT had a lower incidence of breast cancer, than those given HRT alone. It seems that testosterone balances some of the oestrogenic effects, just like progesterone does.
“Women obviously need some testosterone. It is needed for sense of well-being, strength (especially upper body strength), nipple and clitoral sensitivity, body composition and bone density.”
So, what do you do if a woman has symptoms of FADS or if their bioavailable testosterone is too low? Firstly, measure it. If it is low, you treat them. One word of warning - with women you have got to dance delicately around side effects. Too much testosterone has androgenic side effects. Fortunately, there is a sequence of events and the first thing is skin - acne. It could be caused by testosterone or could be caused by DHEA. So, you can play with both. After the patient gets acne, hirsutism, clitoromegaly and a deepening voice will follow. But you do not go through the whole sequence of events, you are aware of it and you decrease the dose. Tell your patients that the gel could cause increased hair growth on the place you rub it in. Thus, advise her to rotate spots and put it on an area where she might shave anyway.
Concluding remarks
Testosterone replacement can provide us with a very powerful tool for maximising quality of life. There is a possibility that it may help to prevent Alzheimer’s disease. It can certainly help the heart and improve body composition. It also has that all-important ability to combat inflammation. Therefore, the benefits are great and the risks are minimal, if proper care is taken.Dr Ron Rothenberg | MD
ABOUT THE AUTHOR
As a pioneer in the field of Anti-Aging Medicine, Ron Rothenberg, MD, was one of the first physicians to be recognised for his expertise to become fully board certified in the specialty.
Dr Rothenberg founded the California HealthSpan Institute in Encinitas, California in 1997 with a commitment to transforming our understanding of and finding treatment for, aging as a disease. Dr Rothenberg is dedicated to the belief that the process of aging can be slowed, stopped or even reserved through existing medical and scientific interventions. Challenging traditional medicine’s approach to treating the symptoms of aging, California HealthSpan’s mission is to create a paradigm shift in the way we view medicine: treat the cause.
He received his MD from Columbia University, College of Physicians and Surgeons in 1970. Dr Rothenberg performed his residency at Los Angeles County-USC Medical Centre and is also board certified in Emergency Medicine. He received academic appointment to the USCD School of Medicine Clinical Faculty in 1997 and was promoted to full Clinical Professor of Preventive and Family Medicine in 1989.
In addition to his work in the field of Anti-Aging medicine, Dr Rothenberg is an Attending Physician and Director of Medical Education at Scrips Memorial Hospital in Encinitas, California. Dr Rothenberg travels extensively to lecture on a variety of topics, which include Anti-Aging Medicine and Emergency Medicine and is the author of Forever Ageless. He has recently been featured in the University of California MD TV series in the shows on Anti-Aging Medicine.
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