Some Characteristics Of Testosterone
Testosterone is principal male androgen, sex hormone and anabolic steroid. It is found not only in humans, but also in many other vertebrates. In males, testosterone is secreted by Leydig cells in testicles, in females by theca cells in ovaries. Small amount is produced also in zona reticularis of adrenal cortex in both genders and in placenta. Chemically , it is white powder, soluble in methanol, name is17beta-Hydroxyandrost-4-en-3-on or 4-Androsten-17beta-ol-3-on, Chemical Abstracts Service number 58-22-0, ATC code G03BA03. It is a controlled substance, in US by Drug Enforcement Administration . It’s inactive epimer difference in configuration of OH at C17 – is called epitestosterone. Testosterone’s biosynthesis starts from cholesterol. Metabolism: up to one tenth of testosterone is converted by 5-alpha reductase to dihydrotestosterone, less than 0.5% by aromatase to estradiol. Most of testosterone is deactivated and excreted as glucoronides.
Figure 1.
Direct Testosterone Assays And Prostate Cancer The Verdict
Probably one of most important reasons for observed discrepancies in testosterone measurements lies in matrix issue, in cross-reactivity. Immunolite assay and Abbot Architect both cross-react with DHEA and give consistently higher values for serum testosterone in range of castration male values . Therefore results of studies, which use direct chemiluminescent testosterone assays in clinical setting cannot be compared to studies, which use chromatography followed by mass spectrometry techniques, because they do not measure the same things.
Inaccuracy of present day direct testosterone assays is already recognized in the field of female and male testosterone replacement, in pediatrics and should be recognized also in the field of prostate cancer. Until indirect testosterone assays applying mass spectroscopy become widely available, publications should set realistic values of castrate levels and precisely state measurement methods used. They may be universally available in the USA, but in Europe, even western university hospitals are not quick in replacing direct immuno-assays with gas chromatography methods for example in Ghent they changed only recently, also for reasons like one can not publish any more anything about testosterone without this method. And even mass spectrometry methods show significant errors and inconsistencies.
Urological Referrals For Consideration Of Prostate Biopsy And Rates Of Prostate Biopsy And Diagnosed Prostate Cancer
Twenty-six of the 743 men who had at least one postbaseline PSA measurement had a confirmed increase in adjusted serum PSA of > 1.0 ng/mL, and 1 man had a prostate nodule but not an increase in PSA , outcomes mandating referral to a site or personal urologist for evaluation. Twenty-two men were evaluated by a urologist, and 1 man died of a stroke prior to urological evaluation. Six men underwent prostate biopsies. Five of these men had increases in adjusted PSA > 1.0 ng/mL and a PSA > 4.0 ng/mL. The sixth man had a prostate nodule but not an increase in serum PSA. Reasons that the urologists did not perform a biopsy included adjusted PSA increase < 1.0 ng/mL when repeated by the urologist , PSA less than age-related PSA criterion , normal digital rectal examination by urologist , and refusal of biopsy .
Of the four men treated with testosterone who underwent biopsy, three had cancer, two of which were Gleason 4+4 = 8 . Of the two men treated with placebo who underwent biopsy, one had cancer.
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What Are The Side Effects Of Hormone Therapy For Prostate Cancer
Because androgens affect many other organs besides the prostate, ADT can have a wide range of side effects , including:
- loss of interest in sex
Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer Trial 30891. Journal of Clinical Oncology 2006 24:18681876.
Zelefsky MJ, Eastham JA, Sartor AO. Castration-Resistant Prostate Cancer. In: Vincent T. DeVita J, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 9e. Philadelphia, PA: Lippincott Williams & Wilkins 2011.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. European Urology 2021 79:150158.
Different Roles Of Testosterone In The Onset And Progression Of Pca
To date, no documented epidemiological studies have distinguished testosterone as a cause of PCa from a promotor of PCa growth. One advantage of our dynamic model is that it can be used to assess the role of testosterone in the onset of PCa. As the model suggests, the prostatic carcinogenesis may be a process by which the normal prostate cells first adjust themselves to progressive declining testosterone levels at the cellular and receptor levels. As testosterone levels fall below the threshold when normal prostate cells are not able to make additional adjustments without mutations, some of the normal prostate cells may evolve into cancer cells. If additional testosterone is added before reaching the threshold level, it may change the course of the disease. Among the mutated cancer cells, some of them may become testosterone sensitive and increases in testosterone may therefore promote these cancer cells to grow. This notion is supported by evidence that castration can inhibit PCa progression , while administration of exogenous testosterone can promote PCa progression . Therefore, our dynamic model can also be used to interpret the seemingly conflicted findings that higher testosterone can prevent PCa onset but promote PCa progression after the disease occurs.
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Androgens And Prostate Physiology
Androgens play a critical role in male sexual development and prostate physiology. The two principal androgens in men are testosterone, produced by testicular Leydig cells, and dihydrotestosterone , produced from testosterone in peripheral tissues by 5- reductase. In circulation, testosterone is bound primarily to sex hormone-binding globulin while the unbound, or free testosterone, is the most bioavailable and active form. In the second trimester, fetal testosterone induces development of the epididymis, vas deferens and seminal vesicles, while DHT mediates development of the prostate, urethra and external genitalia . From birth through puberty, the prostate remains small and immature, while in postpubertal males the surge in androgens drives gland development and an increase in prostate volume up to 10 times its prepubertal size . DHT also plays a well-established role in promoting continued growth of the adult prostate, leading to benign prostatic hypertrophy .
S For Serum Testosterone Measurement
With introduction of indirect RIA techniques to measure serum testosterone in 1970ties and later automated chemiluminescent assays, serum testosterone values became widely available to practicing urologists.
In direct RIA methods, principle is the same, only marking of competing antigen is performed with radioactive substance instead of alkaline phosphatase or other enzymatic, fluorescence-based technique. Large variability was observed for direct RIA methods . In indirect RIA methods, quantification follows organic solvent extraction and purification steps with monitoring of procedural losses. Although correlations between indirect RIA and mass spectrometry methods are good , absolute concentrations were reported to be significantly higher, probably , due to cross-reaction of immunoreactive material .
Indirect assays are not available any more in our practice. Main method for serum testosterone determination in most present day clinical laboratories around the world is still direct automated chemiluminescent assay . This assay mixes antibodies directly with serum and skips extraction step. This holds true for all direct assays, not only chemiluminescent but also radio-immuno based.
Some characteristics of testosterone assays are summarized in Table 2.
| Type |
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Jeffrey Turner Md Prostate Oncology Specialists Marina Del Rey California
Low testosterone , or hypogonadism, is typically encountered by men when they arrive at middle or late stages of life. The symptoms are increased body fat, weight gain, low sex drive, fatigue, anemia, depression, poor memory, osteoporosis, and a higher risk of diabetes. The first step when considering whether testosterone replacement is appropriate is to determine if the cause is primary or secondary. Primary hypogonadism is when the testicles themselves fail to produce adequate amounts of testosterone. Secondary hypogonadism occurs when the pituitary gland stops producing sufficient amounts of LH , the hormonal factor that stimulates the testicles to produce testosterone.
When a diagnosis of primary hypogonadism is made, direct replacement with testosterone is a reasonable course of action. In secondary hypogonadism, men can take medications, such as Clomid, which work by stimulating the pituitary gland to produce more LH, which in turn stimulates increased production of testosterone from the testicles.
Why do we care about the specific methodology of increasing testosterone? Because long-term testosterone replacement can further suppress any residual testosterone production from the testicles, causing testicular atrophy. By stimulating natural production with Clomid, the functionality of the testicles is maintained in a natural state.
Identify Your Prostate Cancer
To this point, much of what we have discussed is fairly standard and many endocrinologists and general physicians are familiar with the delivery of testosterone treatment to men without prostate cancer. The trickier situation, as noted above, is in men with active or previously treated prostate cancer. After all, testosterone reduction therapy is one of the most popular ways to counteract prostate cancer. How, therefore, can the administration of additional testosterone in men with prostate cancer not be harmful? The answer is that the type of prostate cancer needs to be clearly defined.
Active prostate cancer basically can be divided into two broad categoriesthe harmless types , and the more consequential types, which are graded from seven through ten. Additional factors such as PSA and the results of various scans may also affect decision making. In most cases, evaluation by a prostate cancer expert will probably be necessary to make a final determination about the safety of giving testosterone treatment to someone who has a history of prostate cancer.
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Testosterone Levels Alone May Not Hold The Key
However, while this research gives some interesting clues about factors involved in causing prostate cancer in the first place which will undoubtedly prove useful in working out how to one day prevent the disease from occurring it also raised more difficult questions.
Thats because although men with lower levels of testosterone were less likely to develop prostate cancer, once they did, it was more likely to be an aggressive form of the disease. So far, we dont have any answers as to why this might be, but it adds yet another layer of complexity to the mystery of prostate cancer development, and opens another avenue of investigation to the scientists set on unravelling these sorts of clues. It also suggests that testosterone levels alone will not hold the key to the causes of prostate cancer development, and that the link between male sex hormones and cancer development may well be more complicated than we previously imagined.
Dr Matthew Hobbs, Deputy Director of Research at Prostate Cancer UK said: This research gives us some important clues about the role that testosterone might play in triggering prostate cancer. Its particularly interesting that men in this study with the lowest levels of the hormone were less likely to get prostate cancer, but if they were diagnosed, it was more likely to be aggressive. This is clearly a complex effect and more research is needed to understand it.
Physical Activity And Risk Of Pca
Studies have shown that both occupational and leisurely physical activity can reduce the risk of PCa . Many studies have also found that physical activity can increase testosterone levels, particularly among older men , contradicting the current paradigm . Our dynamic model more fully allows for the idea that physical activity prevents PCa by increasing testosterone levels, slowing down the age-related declines in testosterone.
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Testosterone Supplementation After Prostate Cancer
Two experts examine the pros and cons of this controversial practice
At some point in their 40s, mens testosterone production begins to slow. By some estimates, levels of this hormone drop by about 1% a year. As men get into their 50s, 60s, and beyond, they may start to have signs and symptoms of low testosterone. These include reduced sex drive and sense of vitality, erectile dysfunction, decreased energy, lower muscle mass and bone density, and anemia. When severe, these signs and symptoms characterize a condition called hypogonadism.
Researchers estimate that hypogonadism affects two to six million men in the United States. Yet it is an underdiagnosed problem, with only about 5% of those affected receiving treatment, according to the FDA. Deciding which patients should receive testosterone supplementation has proved tricky, however. For example, little consensus exists on what constitutes low testosterone. In addition, some men may have low blood levels of testosterone but not experience any symptoms. And few large, randomized studies on the long-term risks or benefits of testosterone supplementation have been completed.
Massspectrometric Assay Of Testosterone And Dihydrotestosterone
Detailed procedures are described elsewhere,, and we here briefly describe the procedures with some modifications. For extraction of steroids, cultured LNCaP cells and prostate tissues were suspended in 1 mL of distilled water and homogenized by UltraTurrax homogenizer. For determination of the concentration of testosterone and DHT, the LCMS/MS system, which consists of an Agilent 1290 Infinity LC System and an API5000 triple stage quadrupole mass spectrometer , were employed. MS analysis was operated with electro spray ionization in the positiveion mode. In the multiple reaction monitoring mode, the instrument monitored the m/z transition, from 394 to 253 for Tpicolinoyl anf from 396 to 203 for DHTpicolinoyl. The limits of quantification were 1 pg for testosterone and DHT.
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Human Prostate Cancer Cell Lines And Cell Culture
Human prostate cancer cell lines LNCaP and 22Rv1 were obtained from the American Type Culture Collection , cultured in 10cm diameter dishes with RPMI 1640 Medium containing 10% FBS and 1% penicillinstreptomycin at 37°C under 5% CO2, and passaged with TrypLE Select every 3 days to maintain the cell monolayer. For investigation of testosterone and DHT levels in LNCaP cells, charcoal stripped FBS was used in the medium instead of FBS for 24 hours culture before curcumin treatment. LNCaP and 22Rv1 cells were characterized for androgen receptor expression. We obtained an effective preparation of curcumin , a nanoparticle colloidal dispersion with improved oral bioavailability . Curcumin was dissolved in ethanol at a concentration of 10 mmol/L, and was stored at 20°C until use.
What Are Male Sex Hormones
Hormones are substances that are made by glands in the body. Hormones circulate in the bloodstream and control the actions of certain cells or organs.
Androgens are a class of hormones that control the development and maintenance of male characteristics. The most abundant androgens in men are testosterone and dihydrotestosterone .
Androgens are required for normal growth and function of the prostate, a gland in the male reproductive system that helps make semen. Androgens are also necessary for prostate cancers to grow. Androgens promote the growth of both normal and cancerous prostate cells by binding to and activating the androgen receptor, a protein that is expressed in prostate cells . Once activated, the androgen receptor stimulates the expression of specific genes that cause prostate cells to grow .
Almost all testosterone is produced in the testicles a small amount is produced by the adrenal glands. Although prostate cells do not normally make testosterone, some prostate cancer cells acquire the ability to do so .
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The Dynamic Model And The Effect Of Age On Pca
After the age of 50, the incidence of PCa increases exponentially with age . Prior studies have yielded rich data regarding the age patterns of testosterone. Testosterone levels are increased in pubertal adolescence, then peak between 30-40 years, and subsequently falling thereafter at the rate of 23 % per year . In some men, normal prostate cells develop into tumor cells with age after testosterone level reaches blow a certain level , leading to PCa. Figure illustrates the parallels of PCa development and declining testosterone levels. Studies of age patterns of testosterone levels suggest that only a small proportion of individuals have testosterone levels below the threshold before age 50. Consequently, PCa risk is very low among this young population. However, after age 50, the proportion of individuals with testosterone levels below the threshold increases dramatically with each. As a result, PCa risk also increases exponentially.
Additional Benefit To Hormone Therapy
The scientists believe that the sugar groups added to the cell surface through glycosylation make the cancer cells more likely to survive and spread, making the cancer more aggressive. These results suggest that hormone therapy might benefit men by lowering the production of these glycans, thereby weakening the cancer cells. However, by targeting the genes involved in glycosylation directly, it could offer a new approach to treating prostate cancer.
Although changes in glycosylation are fairly common in cancer, this finding helps us understand what is driving these changes in prostate cancer. This could open new doors to help diagnose more aggressive cancers earlier and identify which men might one day benefit from drugs developed to block the glycosylation process.
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Hormone Therapy For Prostate Cancer
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Hormone therapy is also called androgen suppression therapy. The goal is to reduce levels of male hormones, called androgens, in the body, or to stop them from fueling prostate cancer cells.
Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone . Most androgen is made by the testicles, but the adrenal glands as well as the prostate cancer itself, can also make a fair amount. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.