Natural relief from the discomfort of prostate related symptoms.

The Prostate Gland in Health and Disease

Overview

Both the prostate's functions and its vulnerabilities arise from its place in male anatomy.  The prostate is a walnut-sized chestnut-shaped gland which is strategically located at the point at which the bladder gives rise to the urethra, the outlet for urine.  Figure 3 shows the prostate as it lies below the bladder and surrounds the urethra.  The urethra is easily recognized as the tube which exits via the penis and allows urination.  Figure 4 shows a second tubule (the vas deferens, one of the two ductus deferens) which leads from the testes, around the bladder, and into the prostate.

The more usual and unglamorous role of the prostate is to control the outflow of urine from the bladder and into the urethra.  Urination requires that the prostate's fibromuscular tissue, about 30% of its total tissue mass, contract to open (that is, to dilate) the urethral tubing as it passes through the gland.  It is the contraction of the prostate which allows fluid to pass through the urethra and, ultimately, through the penis to the outside.  (The rest of the urethral structure, which is lined with smooth muscle, remains normally contracted to act as a sphincter and must relax to allow the flow of urine.)  This role is more properly that of an organ than that of a gland.

As a gland, the prostate is capable of secreting a milky, mildly alkaline fluid with some special functions which involve the sperm.  As they mature, sperm from the testes flow up the muscle-walled vas deferens, around the bladder and into the seminal vesicles, where they are stored.  The seminal vesicles produce their own seminal fluid which nourishes and gives volume to the sperm.  During sexual excitement the seminal vesicles empty their contents into the prostate, which, in turn, adds its own prostatic fluid to this mixture.  Some prostatic fluid precedes ejaculation, but most of the released fluid is added to the sperm and seminal fluid to constitute the semen.  Only about 5% of the final mixture comprising the ejaculate is composed of actual sperm.  Prostatic fluid is both a lubricant and a carrier of sperm and constitutes about 20% of the volume of the semen.  The muscles of the prostate are very active in the expulsion of semen from the body at sexual climax.  The stimulation of the prostate which activates ejaculation is responsible for much of the intense pleasure which immediately precedes ejaculation.

In an adult male, the prostate usually weighs about 20 grams.  Almost all of this mass develops during puberty in response to hormonal changes associated with maturation. The prostate literally doubles in size during puberty.  If a man is lucky, and some are, the prostate never again undergoes any changes in size.  Unfortunately, of men between the age of 40 and 59, nearly 60% can be shown to already be suffering from benign prostatic hyperplasia. [F. Hinman, Benign Prostatic Hypertrophy. (New York: Springer-Verlag, 1983.)]  This usually does not present a noticeable problem until after the age of 50; by the age of 80, however, some 85% of all men suffer from one or more symptoms of BPH.

Figure 3: The Male Reproductive System

Figure 4 gives a clearer view of the prostate's relationship to these organs and tubules.

Figure 4: The Bladder and Prostate

Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia (formerly called hypertrophy) in some ways is the male equivalent of menopause.  The primary effect of BPH is a progressive decrease in the ability to empty the bladder as the prostate enlarges and applies pressure to the urethra.  Retained urine from this obstruction at first can interfere with sleep as the sufferer wakes up in the middle of the night.  At other times, pressure may make it impossible to properly control urine flow (incontinence).  Retained urine in the bladder can allow bacterial growth and infection.  Urine may flow back up the tubules to the kidneys and cause infection there.  In severe cases of retention, urine even can find its way into the blood (uraemia) with toxic consequences.  The American Urological Association Symptom Index is now a standard assessment for BPH serverity.  It is reproduced here.  Fortunately, prostate problems tend to worsen rather slowly, and this allows a window for applying herbal and nutritional measures.  However, severe prostatism warrants medical consultation.

Nonhormonal Sources of Prostate Discomfort, Dysfunction and Enlargement

Not all sources of prostate enlargement arise from hormonal alterations typical of aging, nor are all sources benign.  Painful or chronic problems involving urine flow or the urogenital area therefore may require the help of a physician.  Several conditions other than BPH can lead to prostate enlargement and to a blockage of urine flow.

The first of these conditions is really a catchall which goes under the general name of prostatitis.  This is an inflammation of the prostate and may involve considerable pain, whereas BPH may not involve any pain at all (as opposed to discomfort).  Prostatitis is fairly common in adult males and has been classified into four types. [Meares EM, Jr., "Prostatitis and Related Disorders," in Campbell's Urology, 6th edition, ed. by P. C. Waslsh, et al. Philadelphia, PA: W. B. Saunders Company, 1992, pp. 807-822.]  Only at most 5 percent of all cases consist of either acute or chronic bacterial prostatitis.  Nonbacterial prostatitis comprises 64 percent of cases and prostatodynia makes up another 31 percent.

Acute prostatitis is the result of bacterial infection, usually E. coli, and typically begins with the fever, chills and other symptoms which bacterial infections bring on.  Pain in the lower back and in the area between the scrotum and the anus are typical, as is difficult and/or painful urination, increased frequency of urination, etc.  Acute prostatitis is most commonly found in young sexually active men, and this may be the source of infection, especially if there are many different sexual partners.  Treatment includes antibiotics and is usually effective.

Chronic prostatitis can be related to failed treatment of acute prostatitis or it may develop on its own.  It involves frequently recurrent low-level infections of the prostate which usually involve the same strain of bacteria.  Symptoms include frequent and painful urination and nocturia (waking several times during the night to urinate).  Stones or calculi made up of urinary components often are found in the prostatic ducts, and this implies a reflux of urine into these areas.  Antibiotics fail as a treatment in cases of chronic prostatitis because they cannot eliminate the bacteria which are found in these stones, hence there is present a constant source for reinfection.  Another factor often found is a lack of zinc in prostatic fluid.  Prostatic fluid is continuously released and contains a potent antibacterial factor which includes free zinc as the most active ingredient.  Men with low levels of zinc in their prostatic fluid seem especially prone to chronic prostatitis.

Nonbacterial prostatitis is the most common of the prostatic conditions, but its cause has not been isolated.  It is characterized by an unusally high number and activity of inflammatory cells in the prostate.  The resulting inflammation resembles that found in chronic prostatitis, but there is neither a history of infection nor do cultures (for bacteria) prove positive.  Along with the symptoms found in bacterial infections, post-ejaculatory pain and discomfort are typical of this form of prostatitis.  Conventional medical treatments do not yield good results. Abstaining from alcohol and spicy foods helps in some cases.

Prostatodynia, which is most common in young and middle aged men, presents many symptoms similar to the above, but lacks the excessive number of inflammatory cells.  Just as nonbacterial prostatitis has some symptoms which are peculiar to it, so, too, does prostatodynia.  In particular, pain and/or discomfort in the groin, perineum, testicles, lower back and penis seem to characterize this condition.  Smooth muscle spasms in the prostatic portion of the urethra and in the neck of the bladder are at work here.  The subsequent reflux of urine into prostatic and ejaculatory ducts causes a chemically-induced inflammation.  Fatigue in the muscles in the pelvic region and emotional stress appear to be powerful contributory factors in prostatodynia.

Finally, there is always the possibility of prostate cancer.  According to the American Cancer Society, in 1995 this cancer afflicted one out of six American men.  At autopsy, between 10 and 30 percent of men over the age of 50 show some malignant cells in the prostate, and by age 90 the rate approaches 100 percent.  Environment and diet appear to be primary causative factors.  The symptoms of prostate cancer can be very similar to BPH or to the four forms of prostatitis.  Often, prostate cancer gives rise to no symptoms at all.  Only medical examinations are useful in diagnosing prostate cancer, in particular the new blood test for prostatic specific antigen (PSA).  However, even the PSA test gives rise to many both false positives and false negatives.

Hormones and the Prostate

Prostate enlargement is strongly related to normal aging.  Some of the factors involved are quite well understood.  Nevertheless, there also is substantial disagreement about other issues.  BPH can be called an aspect of male menopause because an increased ratio of estrogen to testosterone is active in BPH just as, conversely, in women passing through menopause the ratio of testosterone to estrogen increases.  It is generally accepted that hormone ratios and hormone clearance are involved in BPH, but the exact ways in which these lead to the enlargment has yet to be definitively explained.  As can be seen in Figure 5, testosterone secretion is highly regulated by way of feedback loops involving the pituitary gland and the hypothalamus.  Inasmuch as renewed prostate growth appears in later life at the point at which actual testosterone production is in significant decline, it is plausible to suspect that secretory signals may play a role in alterring the clearance of testosterone from the tissues affected.

Testosterone, the "male" hormone, is at its peak during adolescence.  It decreases thereafter, and the rate of decrease sharpens by about age 50.  The decline in testosterone production typically calls into play the compensatory release of other hormones which are stimulants to testosterone production.  These cannot prevent the decline in testosterone levels, but they can lead to an elevated rate of transformation of testosterone into 5-alpha-dihydrotestosterone (DHT) and/or to the increased binding and/or to the decreased clearance of DHT from prostate cells.  Testosterone is converted to DHT by the enzyme 5-alpha-reductase.  Ultimately, it is DHT's actions which cause the enlargement of the prostate.  DHT binds to specific receptors on the prostate cells usually referred to as androgen receptors.  It then is transported into the nucleus of these cells where it attaches to the DNA and ultimately turns on prostate growth.  As will be explored in more detail below, current research indicates that DHT is a necessary, but not a sufficient cause in the etiology of BPH.

Figure 5: Glandular Regulation of Androgen Secretion

The above is an illustration of the hypothalamic - pituitary - gonadal axis with site action (X) of gonadotropin-releasing hormone (GnRH) agonists and the sites of the inhibitory (-) and stimulatory (+) actions of testosterone (T).

Figure 6: The Transformation of Testosterone to Dihydrotestosterone (DHT)

One suggested approach to preventing the development of BPH and for reducing symptoms once they have appeared is to inhibit the transformation of testosterone to dihydrotestosterone.

Increases in the levels of estrogens (primarily estradiol) are very important in these developments.  Special enzymes reduce the binding of both testosterone and DHT to prostate cell receptors under normal circumstances.  The unbound androgenic hormones can be excreted more readily from the system than the bound forms.  Recently, authors have begun to argue that in BPH the rate of removal of DHT in particular is diminished and it is this failure to remove testosterone and DHT, and not the merely production of DHT, which primarily encourages the development of BPH.  [Lee C, Kozlowski JM, Grayhack JT, "Etiology of benighn prostatic hyperplasia," Urol Clin North Am 1995 May; 22(2):237-246; also Horton R, "Benign prostatic hyperplasia: a disorder of androgen metabolism in the male." Journal of the American Geriatric Society 1984; 32:380-385.]  Estrogen inhibits the actions of the enzymes which metabolize these androgens into excretable forms.

In a sense, the body might be seen as attempting to compensate for the decrease in its ability to produce testosterone by increasing the actions of the smaller quantity of the hormone which actually is produced.  As is true of the parallel actions of women's bodies during menopause, the secondary modulation of hormonal actions and not the decline in testosterone production per se is the cause of BPH and related symptoms.

Another hormone which plays a significant role in the development of BPH is prolactin.  Prolactin both increases the conversion of testosterone to DHT and the binding of androgens to prostate cells.  Prolactin production itself is increased by stress, alcohol and aging.  One counterweight to prolactin is the hormone melatonin, much in the news as an "anti-aging" hormone.  Significantly, melatonin, which acts to check prolactin production, declines even as prolactin levels increase with age [Lewis AE and Clouatre D. Melatonin and the Biological Clock.  (New Canaan, CT: Keats Publishing, Inc., 1996.)] . This is not to suggest that melatonin supplementation is an answer to BPH, but rather to indicate that various factors related to estrogen binding to receptors in the prostate increase in later life must be considered.

It should be kept in mind that many of the factors found in the various forms of prostatitis may come into play in BPH.  Inflammation is a common and significant element in BPH.  Also of importance are spasms in the smooth muscles which line the urethra and the neck of the bladder, the inability to relax the sphincters constructed of these smooth muscles, a weakened ability to contract the bladder upon command, and so forth and so on.  None of these factors are readily influenced by drug approaches to BPH which are intened specifically to inhibit the conversion of testosterone to DHT.

A Detailed Look at Hormonal and Nonhormonal Factors in BPH

Re-evaluating the Role of Androgens

Although the conversion of testosterone to DHT plays an indisputable role in the development of BPH, the inhibition of this conversion in the treatment of BPH in pharmaceutical trials with the extremely powerful DHT inhibitor finasteride (Proscar™) has proven to be less successful than was expected except in the cases of patients with severely enlarged prostates. [McDonnell JD, et al., "Finasteride, an inhibitor of 5 a-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia," Journal of Clinical Endocrinology and Metabolism 1992, 74(3):505-508; Boyle P, et al., "Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials," Urology 1996, 48(3):398-405.].  Moroever, a number of studies have demonstrated that nontestosterone-based substances secreted by the testes stimulate the growth of prostatic tissues [Lee C, Kozlowski JM, Grayhack JT, "Etiology of benign prostatic hyperplasia," Urol Clin North Am 1995 May; 22(2):237-246.].  Hence although it is clearly the case that men who are severely deficient in androgens (such as through castration or from other causes) do not develop BPH, the actual role of testosterone, DHT and related factors in the development of BPH in normal males is problematic.  Numerous animal experiments have demonstrated the presence of factors other than androgens as being active in prostatic hyperplasia.

Figure 7:  Pathways To Prostatic Hyperplasia and Urinary Urgency

Cell proliferation causes enlargement of the prostate, constricting the urethra and interfering with the normal flow of urine.

As can be seen in Figure 8, until recently the main target sites for therapeutic intervention in cases of BPH have been the actions of 5 a-reductase leading to the production of DHT and/or the DHT / androgen receptor.  (DHT accounts for approximately 95% of the androgens found in the prostate.)  The role of estrogens has not usually been closely considered.  Some authors maintain that the levels of estrogens typically remain largely stable as men age even as testosterone levels fall; other authors find that estradiol levels actually are elevated in men with low testosterone measurements.  [Gann PH, et al., "A prospective study of plasma hormone levels, nonhormonal factors, and development of benign prostatic hyperplasia," Prostate 1995, 26 (1):40-94 finds increased estradiol levels in men with low testosterone was a positive risk factor for advanced BPH.]

The aromatization of dehydroepiandrosterone (DHEA) and androstenedione is a major source of estrogen in males, although it should not be forgotten that the amount of fatty tissues in the body also can have an impact upon circulating estrogen levels. The ratio of testosterone-to-estrogen, as is true of circulating steroid levels in general, is always closely regulated by the body, and changes in the ratio and in the total levels bring into action counterbalancing mechanisms.  For instance, the liver is stimulated by the changes in the testosterone-to-estrogen ratio via the related elevation 17-ß estradiol levels.  The result is an increase in the production of sex hormone binding globulin (SHBG).  Inasmuch as free testosterone has a greater affinity for SHBG than does free estradiol, the net result of this is yet a further decrease in free testosterone levels relative to estrogen levels.  Moreover, aromatase enzymes are particularly active in the tissues of the prostate which directly surround the urethra.  Low testosterone levels, enhanced estrogen levels, and perhaps the increased presence of SHBG itself, appear to upregulate the androgen receptors in the prostate.  Furthermore, estrogen may inhibit the hydroxylation of DHT within the prostate, thus reducing the rate of elimination of this androgen.  Animal studies have shown that giving estrogen together with androgens increases prostate growth relative to that caused by giving androgens alone.

Hence it is now considered to be the case that the elevated ratio of estrogen to testosterone found in aging males increases the activity of androgen receptors in the prostate.  [Droller MJ, "Medical approaches in the management of prostatic disease," British J Urol 1997, 79S:42-52.]  Interestingly, estrogens may directly stimulate the growth of smooth muscle cells both within the prostate and the urethra.  Spasms and excessive tonus in the smooth muscle of the urethra and the neck of the bladder account for many of the urinary difficulties typically found in cases of BPH, and therefore this growth effect is of considerable significance. Difficulties in voiding often reflect an inability to relax the internal and external sphincters of the prostate and bladder.  A recent in vitro test with isolated smooth muscle cells from the prostate showed that whereas DHT stimulates the growth of these cells under laboratory conditions, estradiol, an estrogen, is a much more powerful stimulus.  [Zhang J, et al., "Human prostatic smooth muscle cells in culture: estradiol enhances expression of smooth muscle cell-specific markers," The Prostate 1997, 30:117-129.]

As indicated previously, prolactin is another hormone which influences the production and the binding of DHT.  The exact extent of this influence has not been established.  Similarly, progesterone may play a role in BPH, perhaps one similar to that of estrogens inasmuch as the contents of the progesterone cytosolic and nuclear receptors are linked to those of the estrogen receptors.  Since there are cytosolic and nuclear receptors for androgens, estrogens and progesterone in prostate cells, direct mechanism of action are available.

Nonsteroidal Causal Factors in BPH

Two sets of nonsteroidal elements should be considered as significant factors in BPH.  The first area is of nonandrogenic growth factors.  The second is that of inflammation and alterred immune response.  To these factors should be added alterations in the tonus of the smooth muscles of the prostate, the urethra, etc.

It was long ago suggested that non-androgenic hormones released by the adrenal glands, the hypothalamus and the pituitary may influence the growth of the prostate.  [Grayhack JT, " Pituitary factors influencing growth of the prostate," Natl Cancer Inst Monograph 1963, 12:198-199.]  As is true of prolactin, the levels of luteinizing hormone (LH) , follicle-stimulating hormone (FSH) and perhaps estrogens (in absolute as well as relative terms) increase in males with age.  Recent research has identified various proteins and growth factors, some originating in the testes, as influencing or even initiating the growth of the prostate which characterizes BPH.  Several lines of evidence now indicate that the actions of DHT are at least partially mediated through the mechanisms of these growth factors in the development of BPH.  [Desgrandchamps F, "Clinical relevance of growth factor antagonists in the treatment of benign prostatic hyperplasia," Eur Urol 1997, 32 (1):28-31; Lee C, Kozlowski J and Grayhack J, "Intrinsic and extrinsic factors controlling benign prostatic growth," The Prostate 1997, 31:131-138.]  A clinical drug trial published in 1996 which compared saw palmetto (which at clinical dosages has no effect upon blood DHT levels) and finasteride (which is highly significant as an inhibitor of 5-alpha-reductase activity) concluded that "BPH, which is an age-related disease, is triggered by nonandrogenic factors."

The prostate contains both epithelial and stromal cells.  Renewed prostate growth after puberty may involve one or more of the following: epithelium-derived growth factor (EGF, also called epidermal growth factor), insulin-like growth factors-I and -II (IGF-I, IGF-II), basic fibroblast growth factor (BFGF) and keroatinocyte growth factor (KGF).  The emerging view of BPH is that tissue proliferation within the prostate may require the presence of androgens, but androgens may not be primarily responsible for the resumed growth of the prostate tissues.  This would help to explain the disappointing results found with finasteride (Proscar™) mentioned above.  Furthermore, these growth promoting factors are always balanced by factors which restrain growth, including those which induce programmed cell death.  Transforming growth factor (TGF-ß) is one such compound, and significance must be attached to metabolic and hormonal changes which antagonize the normal growth inhibitory factors found in the prostate.  [Griffiths K, "Molecular control of prostate growth," in Kriby R, et al., eds., Textbook of Benign Prostatic Hyperplasia. (Oxford: Isis Medical Media, 1996) 23-55.]  Indeed, programmed cell death may be a natural regulatory mechanism to maintain prostate homeostasis.

BPH in some cases may be the result of long term inflammatory and immune or autoimmune actions.  Two primary lines of argument have been presented in support of inflammation as causative.  First, the prostate may be subject to invasion by bacteria and perhaps viruses, as mentioned previously.  Immune cells would follow such agents into prostatic tissues in an attempt to eradicate them, and tissue irritation is typical of sites of active immune intervention.  [Wright ET, et al., "Prostatic fluid inflammation in prostatitis," J Urol 1994, 152:2300-2303.]  However, pathogens can evade complete eradication by the immune system because the contents of the tubules of the prostate lie outside the normal circulation.  Stones formed by the deposition of mineral salts and uric acid crystals, for instance, can harbor bacteria which would lie beyond the reach of the immune system.  The low zinc status of most men who suffer from BPH abets chronic low-level infection because free zinc is the most active antibacterial agent found in prostatic fluids.

Another line of argument is that the prostate can become the site of an autoimmune response.  The migration of immune cells into the prostate and their constant activity may lead to the deposition of excessive amount of collagen, etc.  Again, chronic irritation can be seen as an inducer of prostate cell proliferation.  [Wright ET, et al., "Prostatic fluid inflammation in prostatitis," J Urol 1994, 152:2300-2303.]

Changes in the nature and tonus of the smooth muscle tissues of the prostate and the lining of the urethra and the neck of the bladder can contribute dramatically to the symptoms of BPH.  As noted above, elevated estrogen levels, which can be induced locally (as opposed to in the circulation in general) by the activity of aromatase enzymes, have been shown in vitro to stimulate the growth of these smooth muscle tissues.  Moreover, these same tissues are under sympathetic autonomic control and replete with adrenergic fibers and alpha-1 receptors.  Thus changes in contractile tonus stemming from increased contractile strength and/or increased adrenergic stimulation will worsen the symptoms of BPH and can even act as contributory etiological agents in BPH.

As can be seen, an increase in urethral resistance may represent more than merely a mechanical obstruction of the urethra by the impingement of an enlarging prostate upon the tubule which it surrounds.  Alterations in the contractility of the smooth muscle may play a large role, as well.  If the bladder sphincter and the urethral wall cannot readily relax, this can lead to bladder irritability.  The detrusor muscle of the bladder initially can compensate for the increased resistance by increasing in size, but this is not a good solution for the body.  Elevated resistance not only causes the destrusor muscle to hypertrophy, but it also induces the deposition of more collagen within the bladder wall.  As a consequence, there is a general thickening of the wall and a loss of elasticity.  The functional capacity of the bladder consequently declines and irritability increases.  The classic BPH symptom of feeling "ready to go" yet being unable to void is the ultimate upshot of this chain of events.

Figure 8:  Factors Influencing Benign Prostatic Hyperplasia

Notably, adrenergic antagonists and alpha-1 receptor blocking drugs, which were originally developed to treat hypertension, have proven more successful than has finasteride (Proscar™), the inhibitor of 5 a-reductase and the production of DHT.  Blockers of the alpha-1 adrenoceptors relax the smooth muscle tissues of the bladder neck, prostatic urethra, prostate capsule and stroma, thereby reducing the urethral resistance.  Favorable results have been found in about 70% of patients with one of these alpha-1 blockers, terazosin.  [Heimbach D and Müller SC, "Die Behandlung der BPH mit alpha-1-Adrenozeptorantagonisten,"Urologe [A] 1997, 36:18-34; Lepr H, et al., "The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia," N Engl J Med 1996, 335:533-539.]  The alpha-1 blockers are quite fast acting, whereas finasteride typically takes up to six months to deliver its maximal therapeutic benefits.  With both of these classes of drugs, however, side effects are a major problem.

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