Testosterone Replacement Therapy
By Michael Dale Sipes, Jr.
Sine I am a testosterone replacement patient, I have done extensive research regarding the cause of testosterone production failure and the administration of exogenous testosterone itself initially upon my diagnosis. My initial testosterone level was 30 at age 35, a women's normal testosterone level for that age is about 70 ng/dL, which means before testosterone replacement therapy I had a testosterone level less than half that of a women. The decision to place me on testosterone therapy was completely correct and justified on all accounts, beyond my total testosterone level. First the cause the HPA axis or hypothalamic-pituitary-adrenal axis is a part of the neuroendocrine system that regulates the process of testosterone production. The first in this triad consists of the hypothalamus, which in short releases Luteinizing hormone and follicle stimulating hormone. In males LH stimulates the interstitial cells located in the testes to produce testosterone, and FSH basically involves the production of spermatogenesis. If the Hypothalamic system is not working correctly, I.e. the patient's Luteinizing hormone or follicle stimulating hormone is low, then it is a hormonal problem with the pituitary gland and hypothalamic interaction that is at fault. If these levels are normal, then the testes themselves are to blame for the low testosterone level. J. Taylor Hays, M.D., General Internal Medicine, Mayo Clinic has stated that our primary concern with testosterone replacement therapy is with older men and prostate growth and prostate cancer, because the prostate gland grows under the influence of testosterone. While there is not a great deal of evidence that patients who receive testosterone replacement therapy are at increased risk of prostate cancer, this possibility is an unresolved issue. The other thing that I really want to emphasis here is that exogenous testosterone is not more harmful to the body, and thus does not cause more prostate cancer than natural testosterone, it is a myth and here is why and the medical literature to support this claim with references. Testosterone whether natural or endogenous will eventually cause prostrate growth, so denying a young man testosterone therapy in the hopes of preventing prostate cancer 30, 40 or 50 years later is completely unfounded and medically unnecessary and unethical for the patient, since prostrate growth is a natural process for both natural testosterone production and endogenous testosterone. Unethical because it would deny a man his masculinity and basically making him a eunuch who can no longer enjoy the God given ability to enjoy his own sexuality or have a sexual partner. This would also interfere or terminate current relationships or marriages due to the fact the man would no longer be able to have sex. Many ethical questions arise when you consider removing ones sexuality and it is not as simple as it sounds and has profound consequences that ultimately outweigh any risks of testosterone replacement therapy on an individual basis. Since the cause of prostate cancer is not known, large studies have looked at 2 drugs used to treat benign prostatic hyperplasia (BPH),
finasteride (Proscar®) and dutasteride (Avodart®), to see if they might also help lower
prostate cancer risk. In these studies, men taking either drug were less likely to develop
prostate cancer after several years than men getting a placebo. This reemphasizes a point that testosterone it's self is not to blame for prostate cancer, but prostrate growth and inflammation, even taking anti-inflammatory drugs can lower a person's risk of getting prostate cancer. There are other factors that contribute to prostate cancer then just prostrate growth. According to the Urology Care Foundation, The Official Foundation of the American Urological Association; what exactly causes prostate cancer is still unknown; however, the scientific community is conducting research with the hope of finding the answer soon. The current theory is there are many factors that can increase a man's risk for prostate cancer. Some factors are, age, smoking, world region location, ethnicity, family history and diet. In a lecture given by urologist Kenneth Janson, MD, FACS, and Harvard urologist Abe Morgentaler both talk about why giving a patient exogenous testosterone does not increase the risk for prostate cancer. Testosterone, the male hormone, does not cause prostate cancer but is known to feed its growth once cancer has been established. Therefore, some prostate cancer treatments are aimed at blocking the body's production of testosterone. But high levels of testosterone, or testosterone itself is not the reason for the development of prostate cancer, inflammation and other factors such as age, hereditary factors or genetics, diet and environmental factors are. In the past it was accepted belief that raising testosterone would increase the risk of prostate cancer. This was largely because in 1941 Huggins, Hodges and Scott showed that orchiectomy (surgical castration) caused regression of prostate cancer. In 1966 Huggins won the Nobel Prize for "fundamental discoveries concerning the hormone dependence of normal and neoplastic cells in animals, and their practical application to the treatment of human prostatic and breast cancer." In 1981 Fowler and Whitmore re-opened the discussion: they did a study showing that in men with prostate cancer who were treated with chemical castration (i.e. given medicine to shut down all testosterone production), testosterone therapy caused disease progression, just like Huggins and Hodges had shown. However, testosterone therapy in non-castrated men did not cause progression. In 2000, articles from the Massachusetts Male Aging Study were published showing no correlation between PSA and testosterone levels even with testosterone levels up to 2800ng/dL. (For perspective, Age Management Medicine protocols generally do not push levels past 1200ng/dL, so this study used more than double the typical maximum levels for HRT.) In 2002 the Mayo Clinic stated; there is no clinical evidence that testosterone replacement causes prostate cancer. In 2004 Harvard urologists Morgentaler and Rhoden published an article in the New England Journal of Medicine. The article stated: None of the 12 longitudinal population based studies, such as the Physician's Health Study, found any increased risk of prostate cancer in men with higher levels compared to men with lower levels of testosterone. Despite decades of research, there is no compelling evidence that testosterone has a causative role in prostate cancer. There is no compelling evidence to suggest that high testosterone levels or testosterone administration increases the risk of cancer. Prostate cancer becomes more relevant at the time of a man's life when testosterone levels decline. Experienced clinicians aim for the upper normal range, in order to optimize treatment. In 2009, Dr. Morgentaler went a bold step further: he published a case report of an 84-year old attorney who was diagnosed with prostate cancer and decided to not treat it- and to remain on testosterone therapy. After 24 months his PSA decreased and his prostate cancer was deemed stable. Morgentaler proposed the Saturation Theory: in patients with no testosterone (chemically castrated or levels less than 70ng/dL), testosterone replacement may cause disease progression-that first little bit may stimulate receptors on the cancer. HOWEVER, those receptors quickly saturate; therefore if patients are NOT castrated, and have testosterone already circulating, then additional testosterone doesn't stimulate the receptors any further. In 2008 Cornell, Baylor and University of Toronto published a study showing that Testosterone therapy in hypogonadal men after radical prostatectomy for prostate cancer resulted in no increase in PSA and no increase in prostate cancer progression. In 2008, Marks et al published a study showing that tissue levels of Testosterone in the prostate were tested before and after testosterone therapy, and even though blood levels of testosterone went up significantly, there was no change in testosterone levels in the prostate. In 2010 the American Urological Association published work by Morgentaler on 13 patients already diagnosed with Prostate Cancer, who were treated with testosterone replacement and followed for 30 months: they showed no progression of their prostate cancer on subsequent biopsies and no increase in PSA. Furthermore: there is significant evidence to suggest that LOW testosterone INCREASES the risk of prostate cancer:
In 2001 Schatzl showed that lower testosterone levels were associated with more aggressive prostate cancer.
In 2006 Morgentaler and Rhodes published a paper showing that low levels of testosterone actually increase the risk of prostate cancer:
Among 345 hypogonadal men with low levels of total or free testosterone, Prostate cancer was present in more than 1 of 7 of the men even though their PSA was less than 4.0. An increased risk of prostate cancer was associated with more severe reductions in testosterone. This would make sense since young men with very high levels of testosterone do not develop prostate cancer; even in their 30's to their 50's. It's not until the testosterone level decreases significantly that we see the presentation of prostate cancer. It's is not the presence of testosterone that creates the cancer, but the absence, that is completely self-evident and proven if you look at what age prostate cancer begins to become prevalent in men, it correlates with the decrease in testosterone levels. Out of all men over the age of 80, about 80 percent will have prostrate problems or cancer, that is a direct correlation between the markedly decrease in testosterone levels in those patients and not the result of natural testosterone effects over time. Men 40 and younger have fairly high testosterone levels, and thus prostate cancer in men under the age of 40 is very rare. And even more recently, in 2011 Salonia et al found that in men with low testosterone compared with men with normal testosterone levels,
The risk of high-grade prostate cancer was increased by >50% . Local invasion nearly doubled (21% vs. 11%, P < .003), and for men with more severe T deficiency, the risk of high grade cancer tripled (59.5% vs. 19.8%.
Inflammation Damages the Prostate Gland and Contributes To the Development of Prostate Cancer
The prostate gland is very sensitive to inflammation. Urologist Ronald E. Wheeler thinks that the common, ineffectively treated condition chronic prostatitis is a major cause for prostate cancer. Patients with chronic prostatitis often have large numbers of white cells visualized when prostate secretions are examined under a microscope. Possibly lack of effective therapy for chronic prostatitis allows prolonged inflammatory changes in prostate tissue to progress to cancer.
Additionally Dr. Wheeler has noted that elderly males with symptoms of frequent urinating, poor stream, difficulty voiding and discomfort when urinating are often advised to undergo prostate surgery for presumed obstruction to bladder emptying when their symptoms are really due to prostatitis not blockage of urine flow out of the bladder.
Chronic prostatitis may be a sexually transmitted disease as it is often found in young males who have become sexually active. This disease is notorious for failing to respond to antibiotic therapy which suggests that it might have a viral etiology.
An important paper from The Cleveland Clinic has linked genetic mutation with viral infection as a possible cause for prostate cancer. Dr. Eric Klein presented this paper at the 2006 Prostate Cancer Symposium in San Francisco, Ca. Feb 24, 2006. An antiviral protein called RNasel is activated by a viral infection. Prostate cancer tissue from 36 radical prostate surgical operations was studied. Viral sequences for cDNA were looked for by DNA microarray. Tissue localization of viruses was evaluated by immunohistochemistry and fluorescence. In 20 men who were homozygous for RNasel 45% had viral sequences found whereas in 66 controls that had one or no RNasel mutations only 1.5% were observed to have viral sequences. Viral cloning studies revealed that the same (one) virus was identified. This virus named ZMRV is related to the zenotrophic murine leukemia viruses known to cause cancer in mice. The viruses were found in the tissue adjacent to the tumor cells.
Dr. Wheeler has performed another valuable service by slowing down the frantic rush to do radical prostate surgery and radiation implants simply because a patient has an elevated PSA value. Furthermore, the placing of a needle into prostate cancer tissue in the biopsy procedure can cause cancer cells to be found in the blood. This probably is a cause for spread of the cancer in some patients.
Researchers from the Karolinska Institute in Sweden have learned that fish oils, which cut down on inflammation, can reduce the risk of prostate cancer. They studied the dietary histories of 3100 pairs of male twins who provided a dietary history for 34 years. They found out that males who ate 3 or 4 servings of fish weekly had only one half the risk of getting prostate cancer and one third the risk of dying from prostate cancer when compared to men who ate little or no fish. Fish oil is a potent inhibitor of inflammation and when inflammation is suppressed there are fewer stimuli to estrogen to produce rapid cell growth. Other substances which might stop viral inflammation in prostate tissue include the nanotechnology silver product Argentyn 23, Sambuchol, Noni Concentrate, cucurmin and the Essential Oil of Oregano.
Dr. John Lee feels there is potent evidence that testosterone inhibits prostate cancer cell growth. Progesterone is necessary to block the undesirable side effects of unopposed estrogen. The desired ratio of saliva progesterone should be between 200 and 300 times the saliva estradiol level.
What Is The Significance Of PSA Values?
Prostate Specific Antigen is actually produced by both prostate and breast tissue. The function of PSA appears to have been clarified. When there is excessive crowding of prostate cells these cells release PSA. This antigen blocks angiogenesis (new blood vessel formation) of adjacent tissues. This tends to stop cell growth as the rapidly growing cells can no longer get new blood vessels to allow them to continue uncontrolled growth. Thus stopping angiogenesis acts to curtail rapid tumor growth. Men early in the course of their prostate cancer have low testosterone levels and little or no elevation of PSA values. When testosterone levels have been restored to normal in men with prostate cancer cellular energy production is increased and the healthier prostate cells are able to produce more PSA. This leads to a slight increase in PSA values that does not mean that the cancer is growing. It actually means the prostate cell is stronger and again producing PSA which should slow down the cancer by stopping new blood vessel formation.
Restoration of normal levels of progesterone, testosterone and estradiol heals prostate cancer as the hormone abnormalities which caused the cancer no longer exist. Progesterone is a vital part of therapy because it restores normal inhibition of 5-alpha-reductase the enzyme that permits testosterone to be converted into dihydrotestosterone (DHT). This initial undesirable creation of DHT permitted proliferation of prostate cells (benign prostatic hypertrophy BPH) and the subsequent appearance of prostate cancer under the cell growth influence of excess estrogen. Correct administration of progesterone and testosterone can lead to shrinkage of the prostate gland with disappearance of the cell stimulating effects of estrogen and the symptoms of prostatic enlargement.
Elevated PSA values can be found in patients who have enlargement of the prostate gland (Benign Prostatic Hypertrophy), prostatitis and prostate cancer. A surprisingly high percentage of patients have cancer with very low values of PSA supporting the idea low values of PSA are indicative of poor cellular energy secondary to low testosterone levels.
Testosterone is the most potent anabolic (energy creating) hormone. It has been shown to be vital in creating good cardiac performance and muscle strength throughout the body. Testosterone is a direct antagonist of estradiol.
Both progesterone and testosterone promote the p53 gene that leads to normal healthy cell apoptosis (cell death) and helps prevent cancer. Estradiol promotes the Bel-2 gene which is a cancer causing gene that stops apoptosis thus encouraging the development of cancer. The proper relationship of these three hormones is important in preventing and treating cancer. General dosages for men should be age specific and not based upon a range that spans an entire adult life time, say 18 to 75. Normal testosterone levels in men are generally highest from ages 14 to 20, ranging up to over 1000 ng/dl. Testosterone levels drop off slightly starting in the 20s, though in many men, changes aren't that noticeable until after 40. Testosterone has many medical applications when it comes to treating sexual dysfunctions and growth related issues in men. Our body's peak testosterone production during puberty and every year the level of testosterone produced by the body goes down by 2 percent. The body's natural levels of testosterone start dwindling rapidly after the age of 40 and then men face problems like erectile dysfunctions, depression and weakening of bones. Some of the benefits of testosterone injections are:
Increase muscle strength and mass for those who are sick or weak, and people who undergo testosterone injections therapy have experienced instant results. Injectable testosterone is fast reacting as it mixes in the blood stream and shows immediate results; hence testosterone for bodybuilding is very popular. So to improve muscle mass and bone density testosterone injections are one of the most inexpensive options available today. Testosterone injections also improve male libido and are used extensively to treat erectile dysfunctions and also to strengthen erections. They also help the sperm count in men who have a problem with infertility. Undergoing a testosterone replacement therapy will also energize you and give you strength to perform various heavy tasks. Your chance of cardiovascular disease will decline as well as your chance of developing osteoporosis. Decrease in body fat, increase in lean muscle mass and decrease in depression and mood swings. Here are average testosterone levels in healthy men by decade. Measurements are given in nanograms (ng) per deciliter and are representative of the median average testosterone levels, not the low or high range for men aged 20 to 60.
Age 20 to 29: 681 ng/dl
Age 30 to 39: 609 ng/dl
Age 40 to 49: 572 ng/dl
Age 50 to 59: 548 ng/dl
Prostate cancer appears to be caused by excessive exposure to environmental estrogens, inflammation, diet, hereditary factors and age. The poorly understood condition (chronic prostatitis) may be a sexually transmitted disease which does not improve with antibiotic therapy suggesting it could be a viral illness. Using skin formulations of bio-identical progesterone and testosterone can heal and prevent recurrence of prostate cancer by maintaining testosterone, progesterone and estradiol values in a normal range. Perhaps the most dreaded effect of low testosterone in men is loss of sexual function. However, low levels of testosterone have implications in many other aspects of health and wellness, too. There were some experiments done in Europe which indicated that testosterone injections helped in treating cardiovascular diseases. Testosterone injections are also used to treat conditions like hypogonadism and damaged hypothalamus. Low testosterone can result in a drop in bone density, leading to osteoporosis and increased risk of bone fractures. Lower testosterone levels are also associated with irritability, depression, and loss of concentration. Low testosterone can result in increases in body fat levels. In men, excess fat is usually carried in the midsection, and that excess fat increases the risk for heart disease and type 2 diabetes. In conclusion, much must be learned before any conclusive cause can be given for prostate cancer. Other causes are more reasonable than others, but the bottom line is, it's unknown. To initiate testosterone replacement therapy, first the patient must have a luteinizing hormone, follicle stimulating hormone level and testosterone level drawn, preferably in the morning between 6 and 9 am. Then after a base line testosterone level is established, if testosterone replacement therapy is indicated treatment can be initiated. For beginning therapy 200mg twice a month delivered by injection into the outer thigh or gluteus maximum is recommended, and must be injected into a muscle as testosterone injections are released slowly over time to give the patient normal levels of testosterone daily between 6 and 8ng/dl. Exactly 7 weeks after initiation of treatment another testosterone level should be drawn to establish what the patient's testosterone level is and if they need adjustment. This level should also be drawn in the morning between 6 and 9 am. Once a stable replacement therapy is established routine blood work should be performed to include a PSA level every 6 months, digital rectal exam every 3 to 6 months, and raise testosterone levels to the median or median high level based upon the patient's response. Due to testosterone increasing hemoglobin, a CBC or hemoglobin test should be performed every 6 months as a part of routine blood work as well as liver enzymes. Those who do not have a desire for sexual activity longer than a week or 10 days, need reevaluation and levels checked and adjusts slowly, by 50 mg increments and then rechecking the testosterone level in the early morning hours 7 weeks after the adjustment in dosage. For years, the recommendation has been to get a testosterone value early in the morning because levels start to drop after 10 or 11 a.m. But the data behind that recommendation were drawn from healthy young men. Two recent studies showed little change in blood testosterone levels in men 40 and older over the course of the day. One reported no change in average testosterone until after 2 p.m. between 2 and 6 p.m., it went down by 13%, a modest amount, and probably not enough to influence diagnosis. Most guidelines still say it's important to do the test in the morning, but for men 40 and above, it probably doesn't matter much, as long as they get their blood drawn before 5 or 6 p.m. If you want to err or the side of old information then collect the specimen between 6 and 9 am, 3 months after increasing the dosage. All signs of prostate enlargement should be addressed with proper medication to reduce the risk of developing prostate cancer to include frequent digital rectal exams and annual colonoscopies for patients over 50. Over the counter anti-inflammatory drugs taken daily will help combat inflammation of the prostrate and other tissues, thus reducing the chance of developing prostate cancer as well as other inflammatory diseases. Other things to consider are excess estrogen production, resulting in gynecomastia, and testicular shrinkage, all of which can be averted by medications. Reversal of testicular shrinkage is possible and a reduction in breast tissue is possible if the proper drugs are administered. If a doctor does not feel comfortable with this protocol and only wishes to administer Testosterone and no other drugs to combat excess estrogen and testicular shrinkage then the best solution for the patient would be to see an endocrinologist for his testosterone replacement therapy. There are growing data for all-cause mortality that men who have low testosterone die earlier than those who have normal testosterone. A study by the Veterans Administration reported in 2009 showed low testosterone levels were associated with a dramatically increased mortality rate. It's hard to know why that is, but I think we'll be focused on that in the coming years, and it seems that time has come now. The bottom line is this, if you are a young male and you feel fatigued, have a low sex drive or libido, decreased energy, mood problems, reduced muscle mass, excess body fat, testicular shrinkage or genital shrinkage, then you may have a low testosterone level. Sex drive is often not just diminished, it is completely absent altogether. Another warning sign not talked about is a decrease in ejaculatory volume. Testosterone is responsible for the seminal fluids that are expelled during ejaculation, a decrease or absence or testosterone results in a decrease in volume in semen. In addition to shrinkage of testicles, they may feel softer than normal as well. Often men with low testosterone levels will have reduced muscle mass, feel as if they are not as strong as they once were, get tired easy or want to just lay around. In addition to feeling severe fatigue, guys with low testosterone often lose their drive and initiative. Another sign is irritability, mood swings and even depression and less feeling of optimism. Men with low testosterone will say that when their genitals are touched by someone they are attracted to, they do not feel that spark of excitement, the touch just feels wrong to them or they just feel as if their genitals are numb to the touch and feel that usually would induce an erection. The latest research suggest that decreased testosterone levels should be taken seriously, because it could lead to serious illness, such as diabetes, osteoporosis, cardiovascular disease and influence prostate cancer. The good news is that low testosterone levels are easily treated with pills, skin gels, under the skin pellets and injections. One word on the pill form of testosterone, even though that option may seem preferable since taking a pill is extremely easy, oral supplementation of testosterone is not as effective as the injectable version, because the body absorbs it quickly from the intestines and the liver breaks it into components that are not useful. Also, it can cause liver damage and a side effect that jells, pellet inserts and injections do not. I prefer injections because they are the 'gold standard' for replacement, and they are easy and relatively painless after the first few injections, but most importantly injections give me even testosterone levels throughout the entire month. The choice of course is yours to make which replacement option is best suited for you. If you do decide on Testosterone injections, for better results it is recommended but unknown to most doctor's that weekly injections rather than bi-weekly or monthly injection are more desirable. They allow for a more consistent and even testosterone level throughout the month without the very high spikes and the lows at the end of the month. Make sure to have your levels checked 3 months after initiating therapy and upon starting therapy have blood work to check your luteinizing hormone and follicle stimulating hormone to see if your low testosterone levels are the result of a testicular problem or a pituitary-hypothalamus gland problem. There are also other things to consider as well, testicular shrinkage and gynecomastia or 'man boobs', all of which can be controlled with safe medications during testosterone replacement therapy. My advice as a TRT (Testosterone Replacement Therapy) patient is to see a good Endocrinologist and not receive TRT from a primary care physician or PA, most do not have the knowledge and training necessary to properly administer testosterone and combat some of its side effects.
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