By by Dana Ohl, M.D. Associate Professor of Surgery University of Michigan
Androgen use is very prevalent in society. Much of this is due to androgen abuse among athletes and bodybuilders, where black market androgen abuse has reached epidemic proportions. Indeed, in various studies of high school boys, it has been found that 4-12% had used androgens at least once (JAMA 27O:12l7, 1993). Androgens have also been prescribed for many conditions by physicians throughout the last several decades.
Despite the prevalence of legal and illegal androgen use, the science of androgen effects has greatly lagged behind the understanding of biological effects of estrogen and indications for estrogen replacement therapy. Female oral contraceptives have been in use for many years, but only recently have we seen studies regarding hormone contraceptive agents in men. Although there are a few very well-defined clinical syndromes of male hypogonadism which require androgen therapy, the use in other clinical situations, such as mild hypogonadism and hypogonadism associated with aging is less well established.
During this lecture, I would hope that some of the mystery of androgen therapy in older men is overcome.
II. Normal Androgen Physiology
Testosterone is present in very low levels in boys prior to puberty. At puberty, pulsatile secretion of GnRH causes the anterior pituitary to produce LH and FSH. Circulating LH induces the Leydig cells of the testis to produce testosterone, with the resultant development of secondary sex characteristics. As the level of testosterone rise in the circulation, there is a negative feedback on the production of GnRH at the hypothalamic level, and LH and FSH at the pituitary level.
A high intratesticular level of testosterone is an absolute prerequisite for sperm production. The levels in the seminiferous tubules remains high due to the proxitimity of production in the Leydig cells, and well as by binding in the tubules by androgen binding-protein (ABP). This binding to ABP probably also prevents fluctuation of the levels, by maintaining a reservoir of hormone immediately available to buffer changes in production. Although testosterone is the only absolute requirement for sperm production, FSH has a promotional effect, and quantitatively normal spermatogenesis requires the action of FSH on the Sertoli cell. When sperm production is proceeding in a quantitatively normal manner, a peptide hormone called inhibin is released into the circulation (also by the Sertoli cell) and is responsible for negative feedback of FSH (but not LH) production by the pituitary.
Circulating testosterone is present in several forms. Testosterone may be present as a free hormone (not bound to any protein) or bound relatively weakly to albumin. The majority of testosterone in circulation, however, is bound to sex hormone binding globulin (SHBC). The testosterone bound to SHBC is not available for biological activity. The free testosterone and that weakly bound to alburnin comprise the so called “bioavailable” testosterone fraction which is responsible for peripheral androgenic effects. Which is the most important measurement in diagnosing hypogonadism, the total T, or free T remains controversial.
Testosterone is converted to other clinically important compounds in the peripheral circulation and/or peripheral tissues. Dihydrotestosterone (DHT) is produced by reduction through the action of 5 reductase, which is present in genital tissue, skin and the prostate. DHT is responsible for prostatic growth and has other trophic effects on the prostatic tissue. Estradiol (E2) is produced by esterification of testosterone. The rate of conversion of T to E2 can be increased in obese men and in men with liver failure. Elevated levels of E2 can down regulate the hypothalamic-pituitary-gonadal axis, resulting in decreased gonadotropin secretion and decreased circulating T levels.
III. Changes in Testosterone Levels With Aging
There is no corollary of the menopause seen in females as men age. The menopause in women is caused by ovarian failure. Although no such similar event of complete testicular failure occurs in men, it has been well established that mean T levels drop progressively with age and the percentage of men with T levels in the abnormal range increases (J Clin Endocrinol Metab 56:1278, 1983;J Clin Endocrinol Metab 73:1016, 1991). When one looks at the levels of bioavailable testosterone, probably more accurate measure of the decreasing androgenic effects, more marked changes may be evident. Other evidence of a relatively hypogonadal state in older men includes elevated LH, as well as an exaggerated response of LH to the administration of GnRH (GnRH stimulation test).
Although T levels drop with aging, it is less clear whether any of the generalized manifestations of aging, such as impotence, osteoporosis, CNS changes, are due to the decrease in circulating androgen. Since it is not established that these age-related changes are due to hormonal deficiencies, the simple presence of a decline in circulating hormones cannot be taken as de facto evidence that hormone replacement therapy will be beneficial in reversing or preventing these changes. An example of this would be in the case of erectile dysfunction. There are certain cases of impotence where the only abnormality seen in testing is a low T level, and in such cases, T replacement therapy may very well be beneficial. However, in the vast majority of older men, one can also identify a very high prevalence of penile arterial insufficiency, tissue dysfunction dysfunction resulting in venous leak, and neuropathic problems, and all of these cases would not be cured simply with hormonal therapy.
IV. Types of Androgen Replacement Therapy.
A. Oral agents –
Testosterone itself cannot be given orally because in the first pass through the liver after oral administration, the breakdown is substantial and very little androgenic effects would be seen. Alkylated forms of testosterone (see table below) are much more resistant to hepatic metabolism and can exert a clinical effect when ingested. Alkylated forms of testosterone are weaker than T itself. The clinical efficacy is further complicated by irregular absorption and varying degrees of hepatic breakdown on the first pass through the liver. Therefore, varying results can be seen when giving these agents. Liver toxicity may be substantial with oral androgens, and such toxicity may range from an elevation of liver enzymes to development of hemorrhagic liver cysts. Liver neoplasms have also been reported in men undergoing oral androgen therapy.
Because of these problems, oral androgen therapy has very little place in the treatment of hypogonadism.
B. Injectable agents-
Testosterone esters (see table) have certain advantages as injectable agents. They are relatively resistant to hepatic breakdown, are released slowly from oil-based carriers, and are hydrolyzed to yield testosterone itself. Therefore, delivery in a long-acting injection is possible, and the biological effects of the injected form of T is indistinguishable from the native hormone. The usual dosage is approximately 100mg. of drug per week is given and the interval can be varied to smooth out these wide swings, i.e. 100mg. every week, 200mg every two weeks, 300mg. every three weeks, etc. acting injection is possible, and the biological effects of the injected form of T is indistinguishable from the native hormone.
Following a testosterone injection, the serum T level rises to high normal or supranormal range for the first few days, followed by a progressive drop until the next injection is administered. The T level may drop below the normal range during this time. These wide swings may cause varying efficacy from the treatment.
V. Testosterone patch therapy
There are currently two available testosterone patch therapies, Testoderm and Androderm. (Please note that Dr. Ohl is a consultant for Alza Pharmaceuticals, and Smith-Kline Beecham for these two products).
Testoderm is a patch that must be worn on the scrotum. In this location skin absorption is increased due to the thin nature of the skin and because of this property of the scrotal skin, permeation enhancers do not need to be placed into the formulation to achieve adequate drug absorption. The potential advantages less potential for skin irritation. Disadvantages include the necessity to shave the scrotal hair and difficulty with adherence of the patch (which has been partially circumvented with the addition of adhesive strips). Another potential disadvantage of Testosderm is the high level of 5-reductase activity in the scrotal skin with the potential of elevation of DHT levels. At this point, however, there is no evidence that an elevation of peripheral DHT levels will have any adverse effects on the prostatic tissue. Testosderm is applied to the scrotum each morning, and comes in 4 and 6 mg dosages.
Androderm is a patch that may be worn anywhere on the body. Because of the increased thickness of the skin and a relative resistance to absorption of the testosterone, it is necessary to place permeation enhancers within the drug vehicle. Because permeation enhancers are present, this patch should never be worn on the scrotal skin where extreme absorption might be seen. Two patches (only one dose available) are worn on flat areas of the skin, not overlying any joints or high movement areas. The pharmacokinetics dictate that Androderm patches are placed in the evening (see below). Patch sites are rotated on a weekly basis so a patch is not placed in the same site anytime during the same week. Advantages of Androderm include non-scrotal application and good adhesion. Disadvantages include a non-discrete location and potential for skin reactions.
Both Androderm and Testoderm, when placed properly at the correct time of day, cause a rise to the mid to upper normal range of serum testosterone in the morning and a decrease to the low normal range in the evening. Therefore, patch therapy mimics the diurnal variation of normal testosterone secretion and appears to be more physiological. Wide swings seen with injection therapy are not seen. Whether or not this more physiological pattern of delivery is more beneficial has not been proven.
TABLE 1. Types of testosterone replacement therapy
Oral (Alkylated forms)
Injectable (Esterified) Testosterone:
Patch therapy (both testosterone)
VI. Potential Benefits of Androgen Replacement Therapy
It has been thought for years that testosterone effect on sexual function is mainly through libido. Although libido is certainly increased by the administration of testosterone in hypogonadal men, there is also some recent experimental evidence in rats to suggest that there may be peripheral effects in penile tissue from testosterone also. Nitric oxide is the primary mediator of penile erection and investigators have shown that nitric oxide synthase in penile tissue is androgen-dependent (Fertil Steril, 63:1101, 1995). Therefore, in the hypogonadal state, it is possible that nitric oxide production in penile tissue may be deficient, with substandard penile smooth muscle relaxation and a poor quality erection. Thus, we may have both central and peripheral effects from testosterone on sexual function.
In men who are identified as having a low testosterone (total and or bioavailable) and have difficulties with erectile function, testosterone therapy may be tried prior to moving on to more invasive tests or therapies. In the event that normal sexual function returns with replacement, then further evaluation is of Testoderm include the hidden site of application and the lack of the permeation enhancers, leading to unnecessary. However, as mentioned above, many elderly men with impotence will have multiple factors leading to their impotence problem and simple hormonal replacement will not result in return of normal sexual activity in most When a trial of testosterone is unable to return a man to normal sexual function, but there are beneficial effects on libido, the wisdom of proceeding on with ongoing androgen therapy is less well established. The physician in this circumstance will have to balance the subjective improvement with potential for adverse effects.
B. Body composition/muscle strength
Androgenic steroids have general effects of making favorable changes in body composition. Several studies in older men have identified decreased fat mass, increased lean body mass, and increased strength ( J Clin Endocrinol Metab 75:1092, 1992; Obesity Res 1:245, 1993; J Am Geratric Soc 41:149, 1993). Supraphysiologic dosages of androgens in normal have been proven to increase muscle strength,”and act synergistically with exercise in this regard (NEJM 335:1, 1996). Larger, as well as long-term outcomes studies regarding the effect of androgens on body composition and strength in older men with hypogonadism are necessary.
Bone mass does decrease as men age. Very little data exists regarding the efficacy of testosterone in reversing or arresting these changes. Some small studies show beneficial effects on bone with androgen therapy (J Clin Endocrinol Metab 75:1092, 1992; J Am Geratric Soc 41:149, 1993), but more research in this area is also necessary. There is no long-term data to assure that androgen therapy will reduce fractures/disability, etc.
D. Cognitive behavior
There is evidence that spatial cognition in older men improves with androgen therapy (Behav Neurosci 108:325, 1994). Another area that is not studied terribly well.
VII. Potential Adverse Effects of Androgen Therapy
As mentioned above, the oral, alkylated forms of testosterone can create a situation of liver toxicity (Semin Liver Dis 7:230, 1987; Liver 42:73, 1992). Since I believe that these oral agents should never be given, this problem can in general be circumvented. There is little evidence that other methods of administration cause liver dysfunction, but I think it is prudent that in men on testosterone therapy, liver function tests be performed at approximately six month intervals.
B. Water retention
Androgen therapy can cause water retention, with the fear of exacerbation of hypertension or inducing or worsening congestive heart failure in older men undergoing such therapy. Weight gain thought to be due to water retention has been demonstrated ( J Clin Endocrinol Metab 75:1092, 1992; JAm Geratr Soc 41:149, 1993), but no study has shown clinically significant pathology due to this retention.
Androgens cause an increase in hematocrit. Two~studies showed a rise in hematocrit between 3.6 and 7.0% in older men receiving T supplementation (J Clin Endocrinol Metab 75:1092, 1992; J Am Ceratr Soc 41:149, 1993). Typically this rise in hematocrit, although measurable, is not clinically significant. Since many older men are also anemic prior to testosterone therapy due to their hypogonadism and/or aging/nutritional changes, the rise in hematocrit may be beneficial.
D. Sleep apnea
Sleep apnea may be worsened in men on testosterone therapy (Clin Endocrinol (Oxf) 22:713, 1985). This may be due to changes in tissue surrounding the posterior pharynx. Therefore, if there is a clinical history of sleep apnea in a man considered for T therapy, this should be investigated and treated prior to institution of therapy.
E. Changes in plasma lipoproteins
This area is perhaps one of the more controversial areas in testosterone replacement therapy. The differences in incidence of atherosclerotic vessel disease between men and women has been ascribed to hormonal differences. Since HDL levels begin to drop in males coincident with the rise of testosterone seen at puberty, the evidence has been compelling. However, a large review of studies that attempted to compare HDL levels with circulating T levels failed to reach. the conclusion that T level is correlated with lower HDL (Diabetes Metab 21:156, 1995). In fact, most of the evidence shows that higher endogenous T levels are associated with a higher HDL, and presumably a lower cardiovascular risk.
This data has been interpreted by some clinicians to indicate that testosterone replacement therapy will cause beneficial changes in HDL. However, when one looks at multiple studies regarding replacing testosterone- in- men who are hypogonadal, a mix of results are seen. Administration of alkylated testosterone derivatives causes a substantial reduction in HDL-C (JAMA 261:1165, 1989). This further adds to the recommendation that these drugs should not be given. When parenteral T esters are administered in weekly 100 mg injections, no change is generally seen, but there is a significant decline in HDL when 200 mg injections are given every 2 weeks (Metabolism 42:446, 1993; Ann Intern Med 116:967, 1992; JAMA 261:1165, 1989). Data on patch therapy is still being generated.
I think it is safe to say that one should view this issue with caution. It would be prudent to get a fasting cholesterol/HDL profile on all hypogonadal men in whom androgen replacement therapy is being suggested and then another profile at three months to look for these potentially unfavorable changes.
F. Prostatic changes
It is clear that without androgens present, prostatic pathology does not develop. Prostatic cancer and benign prostatic hyperplasia never develops in eunuchs. Prostatic diseases represent very clinically significant problems in the elderly and the effect of androgen replacement therapy on the prostate needs to be very carefully considered.
The prostate increases in size during androgen replacement therapy in older men (J Clin Endocrinol Metab 75:1092, 1992). Therefore, symptomatic prostatism may potentially become worse with androgen therapy. Because of this one needs to take a careful voiding history prior to initiation of therapy to uncover such problems.
Prostate cancer has never been proven to be associated with androgen replacement therapy. While there are scattered case reports of development of prostate cancer while on such therapy it is commonly accepted that prostatic cancer which is present (and may be occult when considering androgen replacement therapy) will probably be accelerated by elevation of the serum androgens. In this way an occult prostatic cancer may become apparent during therapy. Surveillance for prostate cancer development and growth is essential during therapy.
Via suppression of the hypothalamic-pituitary-gonadal axis, administration of exogenous androgens results in suppression of spermatogenesis. In many cases, this will lead to complete azoospermia. Indeed, administration of testosterone as a contraceptive agent has been proven to be effective in recent multi-center studies (Lancet 336:955, 1993). Therefore, in all men who are considering treatment of hypogonadism, and in whom fertility is a concern, exogenous androgens must not be given.