posted April 05, 2000 01:43 AM            

Introduction
Andrology is defined as the area of scientific study concerned with the masculine constitution and the diseases of the human male. This implies especially the study of diseases of the male organs of reproduction and aspects of fertility.

Because of the current demographic trends, andrology increasingly will be concerned with problems of aged males, as well as those males in the "crisis decade" (the 50s) entering into an "andropause," or a putative male climacteric. While many critical issues of health and drug therapy of importance to men are not necessarily restricted to that sex, in this article we will consider only those topics that are exclusive to male patients.

Primary and secondary male structures
The primary reproductive organs of the male are the paired male gonads-the testes-which produce not only the male hormones, or androgens, but also the reproductive cells-the spermatozoa, or sperm cells. Gonadal function is activated from the pituitary by hormones called gonadotropins.

In turn, the penis (by which sperm is transferred during coitus) and adjunct organs needed for semen secretion (the seminal vesicles and the prostate) are maintained in development and function by the testicular hormone, testosterone.

In embryogenesis, androgens are responsible for normal virilization of the urogenital tract. At puberty, gonadotropins from the anterior pituitary evoke continuing production of androgens, which in turn act locally on the cells of primary tissues and organs to support their development during puberty and to initiate the production of semen. In addition, they support the development of secondary structures in the male genital tract, such as the prostate.

In general, the androgens are responsible for expression of the male phenotype by also acting systemically, influencing development of not only skeleton, skeletal muscles, and dermal structures but also such other diverse structures as the vocal cords.

Texture of the skin as well as hair follicles of the scalp, beard, and body are under the influence of the male hormonal regulation. Size and shape of the skeleton, the nature of its musculature, and the level of body fat and its distribution are influenced to achieve the classical male habitus with its contrasts to the habitus of the female.

Male endocrinology
The androgens are hormones consisting mainly of testosterone and its reduction product, DHT (dihydrotestosterone). Both of these molecules bind to and activate androgen receptors, but DHT has greater affinity for the receptor and thus comprises a more potent androgen.

Conversion of testosterone occurs under the influence of the enzyme known as 5-alpha-reductase (5AR), which occurs in two forms. Distribution of this enzyme-its levels and the form present-differ across various organs. It is most abundantly present in the prostate, the skin, and the reproductive tissues and organs, making these areas more vulnerable to the effects of androgens. This explains certain later-life, age-related responses to long-term hormone presence, namely, benign prostatic hyperplasia (BPH) and male-pattern baldness-genetically determined, hormone-dependent alopecia. Excess hair growth in older men on areas other than scalp, such as orifices of ears and nose, is another such effect of long-term androgen action.

Testosterone is the predominant circulating form of androgen, occurring primarily (98%-99%) in the globulin-bound form; thus, most of it is unavailable to tissue cells. Another important metabolic route for testosterone is its conversion to estradiol and estrone by enzymes known as the aromatase complex, found most abundantly in adipose tissue, liver, and certain nuclei of the central nervous system. The molecules that have undergone 5-alpha reduction, however, are not susceptible to metabolism to an estrogen.

When the testes diminish their normal output of testosterone, secretion of an androgen from the adrenal cortex, dehydroepiandrosterone (DHEA), may become of increased physiological significance. A recent trend is to attribute some negative aspects of aging to an age-related fall in the secretion of DHEA; these include libido and male sexual behavior, which previously have been considered to be under the exclusive control of complex testosterone-dependent neuroendocrine mechanisms. Research on these mechanisms has not yet yielded the knowledge needed for therapeutic maximization of latter years of life in men. However, modulation of sexual behavior by use of drugs and hormones is increasingly feasible.

Androgenic replacement therapy
Adult-onset deficit or male climacteric. Although therapeutic replacement of sex steroids to deal with the climacteric symptoms of women has been controversial, it is now widely followed. In addition to its aim of reducing risks of some geriatric problems, it carries with it more immediate benefits. For many but not all men, the fact that there is a diminished activity of the hypothalamic-pituitary-testicular axis with age is definite. The question of whether this is a consequence of disease or a feature of the aging process has yet to be fully settled, but recent data support the latter. Regardless of the answer, the principle of hormone replacement therapy has been less well accepted than for women. Despite the clearly defined manifestations of an androgen-deficit syndrome (Table 1), medicine has tended to regard such diminished activity as an inevitable aspect of aging. This view needs serious rethinking.

Table 1 Symptoms and signs of hypogonadism of adult onset Loss of libido Erectile impotence
Increased fatigability Depressed mood
Muscle wasting Osteoporosis
Regression of primary and secondary sexual organs and bodily characteristics, including the male pattern of hair and fat distribution

For men, as for women, there is great concern that sex steroid therapy might amplify the risk for neoplasms of the reproductive system, many of which tend to be hormone-dependent-both benign nodules and prostate carcinoma. There also is a concern for aggravating the risk of BPH and its significantly troublesome symptoms.

Many sources see a contraindication in using androgens in aging men for the purpose of maintaining strength and libido because of an unknown degree of risk elevation for benign or malignant prostate problems. About the prostate, there appears to be very little medical certainty. It is not even agreed whether screening of men 50 years of age or older, by digital exam, transrectal ultrasound, and PSA level, for the presence of either benign or malignant growths in the prostate is more helpful or harmful. Similarly, data are lacking either to refute or to confirm a contraindication in the use of androgens for age-related replacement therapy. And scientific evaluation of whether surgical and/or medical treatment extends life proved impossible because data are inadequate, according to a recent report of a committee of the American College of Physicians.

Testosterone preparations. Injectable formulations of testosterone have been available for many years, but they have not been perceived as replacement therapy related to aging. Hypogonadal states from other origins have been treated, with early products being challenged by new ones having longer and longer duration (Table 2).

Table 2 Available testosterone/androgen preparations Testosterone Transdermal patches 4 mg/d or 6 mg/d
Testosterone cypionate IM injection in oil, 300-400 mg q 4 wks
Testosterone enanthate IM injection in oil, 200-400 mg q 4 wks
Testosterone propionate IM injection in oil, 10-25 mg 2-3 times/wk
Synthetic androgens
Methyltestosterone Oral tabs, 10-40 mg/d
buccal tabs, 5-20 mg/d
Fluoxymesterone Oral tabs, 2-10 mg/d
Nandrolone decanoate IM injection in oil, 100-200 mg/wk
Oxandrolone Oral tabs, 5-10 mg/d
Oxymetholone Oral tabs, 1-5 mg/kg/d

Most recently, products to provide testosterone by transdermal absorption have been marketed. The goal has been to provide a more uniform level of hormone than the pattern of "peaks and valleys" resulting from biweekly or monthly injections.

The first such product required the patch dosage form to be applied to the scrotal skin, which provides an optimal surface for cutaneous absorption because it is thinner than skin in other areas. However, a low convenience factor limits its acceptability.

Effects of hormone replacement via a nonscrotal testosterone transdermal (TTD) patch were studied in a 1997 report. In this multicenter open-label study, 29 hypogonadal men had prostate volume measurements by transrectal ultrasound plus blood levels of prostate specific antigen (PSA) during one year of therapy with this permeation-enhanced TTD system.

The study began with a positive control period in which the men received IM testosterone enanthate (TE), followed by two months of androgen withdrawal (-T), and then (TTD). Mean prostate volume decreased from the TE period to the -T period, then increased from the -T period to the TTD period. Prostate volume correlated with age during all three periods of observation. The maximal prostate size was equal to that found during TE, occurring after month 3 of TTD therapy; prostate size did not increase further during the remaining nine months on TTD.

No patient had symptomatic BPH during the period of treatment. PSA levels fell during androgen withdrawal, compared with levels found during TE use, then rose upon the resumption of androgen therapy with TTD. However, PSA levels during TTD were significantly lower than during TE.

The above findings show that a more physiologic testosterone replacement is achieved in hypogonadal men using a transdermal route than with testosterone depot injections. Prostate size with transdermal therapy did not exceed that seen in normal men, and PSA levels were also normal. This is very supportive of the idea that unfavorable effects on the prostate parameters need not occur with hormone replacement.

Under clinical study at this time is a testosterone gel for transdermal hormone delivery, for which the following advantages are claimed:

Less irritation at the application site

Easier tailoring of dosage

Greater convenience

Steroidal alternatives. There are those who contend that testosterone is not the most favorable choice for replacing a testosterone deficit. This seemingly paradoxical contention is based on the fact that, contrary to other androgenic agents, testosterone has active metabolites with potentially undesirable features. Use of a steroid that doesn't undergo reduction provides desired masculinizing and anabolic effects while not having equivalent negative effects on the prostate that could increase the risk for BPH or malignancy.

One such agent that is under development is 7-alpha-methyl-nortestosterone, while a related agent that has long been marketed is nandrolone decanoate (ND). ND, consisting of nortestosterone, is closely related to testosterone; its oil solution as a depot ester is used by IM injection. Thus, it must be hydrolyzed before the active moiety is released into the circulation, allowing each dose to act for several weeks to a month. This agent is not subject to aromatization to estrogenic metabolites.

Among the advantages suggested for ND therapy are the ability to promote positive metabolic changes-opposing the wasting of muscles and/or bones and reducing excess fatigability-that have been demonstrated in persons requiring treatment because of anemias. This effect should also tend to lessen any depressed mood that may arise from a sense of diminished bodily capabilities. Such advantages contrast with those of 17-alkylated steroids, commonly used orally by body builders, which in many reports have shown a strong tendency to exert an adverse effect on liver function.

This may in part be a consequence of the first-pass effect for oral steroids, which results in hepatic exposure to a higher drug level. Moreover, a 1996 report showed that ND, but not testosterone, exerted the favorable metabolic action of enhancing insulin-independent glucose uptake in normal men.

In another 1996 report, ND at 200 mg weekly for six months did not increase PSA or prostatic acid phosphatase. An earlier test of 100 mg ND weekly for six weeks had shown no negative changes in blood lipids. Thus, while the number of such studies is limited, available data depict ND as having a safe profile of effects on the prostate and liver status. These findings indicate that a patient justifiably could be treated, when a low serum testosterone has been documented and symptomatology shows a clear androgen deficit, by using ND as an alternative to testosterone. "Informed consent" would be an important principle to follow, as the patient should be assisted to weigh the benefit-to-risk ratio according to the level of data currently available.

Reproductive failure
It is estimated that as many as 15% of couples are subfertile-that is, they have difficulties in conceiving-and that in 30% of these cases, the male is the primary source of the infertility.

Two major reasons a man is considered responsible for a conception problem are failure of coitus to enable insemination and failure of sperm to accomplish fertilization of an ovum. The former problem is attributable either to erectile impotence or to coitus without ejaculation, with the reason for reproductive failure evident in that sperm have not been transferred to the female. If insemination appears to occur normally, multiple tests of semen samples for their concentration and for quality with regard to motility of the spermatozoa are needed to assist a diagnosis. Many chemical exposures can have an adverse effect on sperm development (Table 4).

Table 4 Examples of chemicals that inhibit sperm production Anabolic steroids Marijuana
Arsenicals Lead salts
Cadmium salts Nicotine/tobacco use
Cimetidine Nitrofurantoin
Cocaine Sulfasalazine

Ejaculatory failure may be a result of various spinal cord injuries or dysfunctions (Table 5).

Table 5 Conditions responsible for failure of ejaculation
Spinal trauma

Multiple sclerosis

Diabetes mellitus

Transverse myelitis

Congenital anatomical obstruction

Psychogenic disorders

Hypogonadotropic hypogonadism. This term refers to an isolated lack of secretion of gonadotropic hormone by the pituitary because of a failure of hypothalamic secretion of the triggering factor, GnRH (gonadotropin-releasing hormone).

This condition was, until recently, thought to present only concurrently with onset of adolescence and failure of pubertal development, which calls it to medical attention. However, an adult-onset form of this condition was described in February 1997. Ten men ranging in age from 27 to 57 years, who had normal sexual maturation but also idiopathic infertility and sexual dysfunction, were found to lack the normal daily secretory pulses of luteinizing hormone (LH) and consequently have low testosterone output. Use of GnRH therapy reversed their hypogonadism and restored fertility.

Although hypogonadotropic hypogonadism still is an uncommon cause of male infertility, it is now a medically correctable one, at whatever age, by use of gonadotropins or GnRH (Table 6).

Table 6 Regimens for treatment of hypogonadotropic hypogonadism in male infertility

Human chorionic gonadotropin, 200 IU IM 3 times per week for 6 months, followed by menotropins, 37.5 IU each of gonadotropin and FSH IM 3 times per week

Pulsatile gonadotropin-releasing hormone, 4 microM every 3 hours via a portable pump

Idiopathic oligospermia, asthenospermia. The majority of men who present with an infertility problem show no specific identifiable source and are classified as showing idiopathic oligospermia or asthenospermia, conditions reflecting a total sperm count under 50 million per ejaculation or less than 50% motility, respectively. There is currently no documented treatment for this large group of patients, although many medical therapies have been used and success claimed. Unfortunately, however, there generally are no data from controlled clinical trials to validate such claims. Most approaches seek to increase endogenous testosterone or FSH (follicle-stimulating hormone), or both.

Impotent men are frequently treated by means of supplemental androgen preparations (Table 2). Depot products in an oil vehicle for IM dosing monthly have been used for many years. Newer dosage-form technology resulted in transdermal patches, which attempt to attain a more physiological pattern of hormone availability over time.

The results of testosterone treatments and the individual merits of available preparations for impotence, other than in frank hypogonadism, remain controversial. Testosterone in large, exogenous doses has been used with the hope of bringing about a transient suppression of the patient's anterior pituitary, thereby accomplishing a salutary rebound effect on spermatogenesis when dosing and suppression are terminated.

Despite suggestions of improvement in semen quality, there is little or no evidence of a clear-cut benefit on impregnation rate. In a recent study, a series of hypogonadal men took oral testosterone decanoate to assess the effectiveness of such medication on clinical outcome measures. The androgen restored plasma levels of testosterone in all patients and made a measurable improvement in sexual performance in 61% of individuals.

Human chorionic gonadotropin (HCG) given one to three times weekly for 12-15 weeks also has been reported repeatedly to improve semen characteristics. However, no placebo-control data on impregnation rates were available for comparison; thus, it could not be determined whether the rate was altered significantly by HCG.

Increasing the hypothalamic secretion of GnRH by means of antiestrogenic agents-clomiphene citrate and tamoxifen-has been tested against idiopathic oligospermia. The resultant increase in secretion of LH and FSH should increase testosterone output.

However, again there is little or no evidence of an improvement in impregnation rates, although some, but not all, studies found improved semen parameters.

Role of drug therapy in sexual dysfunction
Neuropsychotropic drugs. In evaluating sexual dysfunction in patients using psychotropic drugs, clinicians should first consider other possible etiologies for the problem. In general, drugs that increase dopamine effects amplify sexual desire and behavior, and those increasing serotonin effects inhibit it. Elevated levels of norepinephrine activity have ambiguous effects.

Unwanted sexual side effects have been noted in association with all major classes of psychotropic drugs. Neuroleptic agents especially are often blamed for sexual side effects.

Priapism is possible with neuroleptics and with trazodone; it can be a urological emergency.

Anxiolytics cause mild, nonspecific sexual side effects, as do the mood stabilizers as well. Lithium alone did not seem to have a major effect on sexual function, but combined with a benzodiazepine, it was found to cause sexual dysfunction in 50% of cases.

Antidepressant drugs. In a 1995 study based on chart review, 34 out of 80 male patients reported erectile difficulty, loss of libido, anorgasmia, or delayed ejaculation while receiving antidepressant therapy via selective serotonin reuptake inhibitors (SSRIs-including fluoxetine, paroxetine, sertraline), tricyclic antidepressants (TCAs-nortriptyline, imipramine, amitriptyline, desipramine, and clomipramine), or the monoamine oxidase inhibitor (MAOI) phenelzine. The article emphasized underreporting of antidepressant-associated sexual dysfunction, especially the high incidence of SSRI-associated sexual side effects. The authors concluded that the three SSRIs had an equal potential for sexual side effects, and the rate of adverse effects was low for the atypical antidepressant, bupropion.

Another 1995 paper noted that with serotonergic antidepressants dominating the therapy of depressive disorders, antidepressant-induced sexual side effects had emerged as a major clinical issue. It was concluded that the antidepressants with strong serotonergic effects-SSRIs, clomipramine, and MAOIs-are associated with higher rates of sexual side effects compared with TCAs. Inhibition of orgasm and ejaculation are most prominent with the SSRIs, although alterations in libido, arousal, and erectile capacity are also common.

Treatment strategies for sexual side effects of antidepressants include lower dosage, change to another agent, and use of antagonists to impaired erectile function-e.g., cyproheptadine, yohimbine, amantadine, and buspirone. A 1997 editorial warns that about 20% of men taking SSRIs will experience loss of orgasm, although not of ejaculation, because the two may occur independently.

In a European study, no deterioration of sexual function was reported for bupropion. Improvement in sexual dysfunction was reported for two agents marketed in Europe (but not in the United States)-moclobemide and viloxazine. An atypical antidepressant, trazodone, also had marked stimulating effects on libido and erectile function.

Antihypertensive drugs. Problems with sexual function, long a concern in the treatment of hypertension, may adversely influence patient compliance in therapy. Effect of drug treatment on sexual function was studied in a recently published double-blind, randomized controlled trial of 557 hypertensive men, aged 45 to 69 years, treated with placebo or one of five active drugs (chlorthalidone, acebutolol, amlodipine, doxazosin, or enalapril). At baseline, 14.4% of men reported problems with sexual function, of which 12.2% had problems attaining or maintaining an erection. This correlated positively with systolic pressure, prior antihypertensive drug use, and age. Recovery from impotence among men with problems at baseline was common in all groups, but greatest in the doxazosin group.

Participants receiving chlorthalidone reported a higher rate of erection problems through 24 months than those on placebo (17.1% vs. 8.1%). Incidence was lowest in the doxazosin group but was not significantly different from the placebo group; incidences for acebutolol, amlodipine, and enalapril groups were equal to those for the placebo group.

The similar incidence rates of erectile dysfunction in placebo and most active drug groups suggested a need for great caution in routinely attributing erection problems of hypertensive patients to the drug being used. The study confirms earlier ones that have suggested serious adverse effects of diuretics on sexual function when used as antihypertensives.

In a 1993 study, men were surveyed via telephone when they received a new prescription, and again after 30 days of dosing, for hydrochlorothiazide, furosemide, lisinopril, verapamil, nifedipine, or diltiazem. They were asked questions about their sexual interest, erectile function, orgasmic ability, and sexual satisfaction. It was concluded that furosemide, lisinopril, and verapamil have no effect on sexual function. Hydrochlorothiazide was associated with decreased orgasmic capacity. While not statistically significant, both nifedipine and diltiazem showed a tendency to enhance sexual function, suggesting a need for more study.

Pharmacotherapies for impotence
The broad search for an effective management of erectile dysfunction has led to an increasing level of success. The four drug administration modes are oral administration, injection into the cavernosa of the penis, topical application to the skin of the penis, or intraurethral insertion. Injection has been the most successful, but it has significant adverse consequences. Oral treatment has given encouraging results with centrally and/or peripherally acting drugs used for psychogenic or mild organic impotence. Topical administration has attractive features and has been reported to act favorably.

An ideal drug is not yet in sight. While more and more options for therapy are being used; however, many are not available in the United States.

A summary of these approaches is shown in Table 7.

Table 7 Drugs used in managing impotence, available in U.S. By intracavernosal injection:
Papaverine Phenotolamine Alprostadil
Multidrug mixtures
By oral ingestion:
Bromocriptine Yohimbine Phentolamine
Trazodone Fluoxetine Buspirone
Cyprohepatidine Amantadine
Arginine Naltrexone
By topical application to penis:
Nitroglycerin (NO donor)
Minoxidil Papaverine
Isosorbide (No donor) plus other vasodilators
By intraurethral insertion:
Alprostadil Dinoprostone

In the 1970s and early 1980s, intracavernosal injection of the classical smooth-muscle relaxant papaverine was tested as a means to enhance blood flow into the cavernosa of the penis, thereby to achieve erection for impotent men. The success with this practice was sufficient to spur the development of other entirely different types of compounds for use in the same fashion, including the alpha-1 and -2 blocker, phentolamine, to dilate penile arteries.

Alprostadil for injection. In 1995, alprostadil became the first medication approved in the United States with an indication for the treatment of impotence. Alprostadil is a prostaglandin compound that acts by relaxing the smooth muscle of the penile vasculature to enhance blood flow and the engorgement of the penile cavernosa necessary for an erection. The solution is injected directly into the cavernosa; this gives about an 80% rate of induction of an erection, which may require an onset time of five to 20 minutes.

Responsiveness was found in impotence with multiple etiologies: neurologic, vascular, psychogenic, or mixed. Initial injections must be made in the physician's office to instruct in the proper injection technique, and to titrate proper dosage in order to avoid priapism. Adverse effects include pain at injection site (37%), excess duration of erection, and local fibrosis. Use of alprostadil is contraindicated for men who are predisposed to priapism, sickle cell anemia, certain cancers, penile malformation, or penile implants. It has at times been used as a component of synergistic multidrug mixtures to help avert adverse side effects through the use of lower doses of each component.

Nitric oxide, topical vasodilators. There is now evidence that nitric oxide (NO) may be the normal physiological mediator of vasodilation and penile engorgement for erection. NO is an important endogenous smooth-muscle relaxant derived from the amino acid arginine by an oxidative enzyme, NO synthetase. Drugs acting as donors or precursors of NO may become important new agents for treating impotence; oral arginine has been used for this reason. Moreover, it is now known that the classical vasodilator agents, nitroglycerin and organic nitro compounds, act by releasing NO.

Topical application of nitroglycerin to the penis was found to evoke an erection in impotent men. However, vaginal transfer of the compound may cause headache in a woman if a condom is not used. A report from outside the United States cites successful use of isosorbide dinitrate plus aminophylline and coergocrine mesylate in a topical form. Benefit was greatest for psychogenic etiology.

Central dopaminergics. The mechanism for benefits of cyproheptadine, amantadine, and buspirone, alluded to above, is believed to be that of enhancing brain dopaminergic system(s) subserving sexual feelings and functions. Parallel can be seen in sexuality-enhancing side effects of levodopa when used in Parkinson's disease patients. No such agent has an approved indication for treating impotence.

Trazodone, yohimbine. Anecdotal reports of an increase in libido and sexual function in patients on the atypical antidepressant, trazodone, led to its being used empirically in impotent patients. From 1989 to 1994, 182 patients aged 26 to 85 years (mean, 60 years) were given trazodone for impotence therapy.

Those treated with trazodone starting at 25 mg daily for at least two consecutive months were followed by a questionnaire on perceived improvement in potency, sexual function, and side effects. Of 127 patients under 60 years and having no known risk factor for impotence, 78% showed improved potency; smokers and patients above 60 years with peripheral vascular disease responded poorly.

Probability for a favorable response to trazodone decreased with increasing duration of impotence. Of patients with a duration of impotence less than 12 months, 48% reported a positive outcome. Only 16% of patients with a duration of erectile dysfunction longer than five years reported improvement in erections and sexual function. Trazodone was well tolerated, as 62% reported no side effects. Despite the limitations of a nonrandomized, retrospective study, trazodone appears to benefit younger patients with erectile dysfunction having few known risk factors. A prospective placebo-controlled trial is needed to confirm these observations.

The alkaloid yohimbine has long been regarded as an effective systemic therapy for impotence because of a peripheral alpha-2 adrenergic blocking action. However, the action of yohimbine now appears to be exerted in the central nervous system, where it may act through several neurohumoral systems. In a recent open study, it was found able to reverse the adverse action of fluoxetine on sexual function. (Paradoxically, fluoxetine itself has been found to restore sexual function in some male patients.) It is likely that placebo effect contributes to the reputation of yohimbine, as many products containing yohimbine have seemingly too low a dosage for effectiveness.

Moreover, yohimbine plus trazodone was tested for effectiveness and safety in 63 cases of psychogenic impotence in a randomized, double-blind, placebo-controlled crossover study comparing placebo, yohimbine (15 mg/day orally), and trazodone (50 mg/day orally). Treatment consisted of two eight-week courses in which patients first received placebo for eight weeks and then the drug combination. Positive clinical responses (complete and partial) occurred in 71% of patients at the end of the drug phase, which exceeded significantly the response for placebo. At three- and six-month follow-ups, more than 50% of patients had maintained positive results. Minor adverse effects were seen in 11% of patients with drug versus 4% for placebo.

Ginseng. Among the array of natural products touted for restoring a waning male libido, the most valued is ginseng root. A quote from a grower and distributor of American ginseng is instructive: "Ginseng's value is mainly as a preventative. It should be taken over a long period of time to stimulate rejuvenation and virility." We have seen no data that permit scientific validation of such alleged actions, although there undoubtedly are pharmacologically active compounds in the plant.

Other indications for androgenic therapy
In preadolescence and early adolescence, there may be occasion for a limited duration of androgen therapy for cryptorchidism (undescended testes), when the gonads fail to descend from the body cavity into the scrotum. Male patients with chronic liver disease usually have low plasma testosterone levels and experience loss of libido and potency. This is also true for male patients with idiopathic hemochromatosis (IHC). Thus, testosterone was tested in 10 patients with IHC in a 1992 study. A 250-mg dose of testosterone enanthate (TE) raised plasma testosterone by more than four times and rapidly restored sense of well-being, libido, and potency without harm to liver function. Testosterone is especially indicated to maintain quality of life in younger patients.

Finally, in the third world, another use for androgens is to produce a state of aspermatogenesis by inhibiting gonadotropin secretion as a means of contraception.

Pathologic importance of the prostate
The prostate is seldom considered until it causes trouble, usually in men past the age of 50 years. The problem may be acute or chronic infection, which may occur at younger as well as older ages; the age-related hyperplastic enlargement (benign prostatic hyperplasia, or BPH), a nodular benign tumor, or a malignant carcinoma. Bacterial infection of the prostate is often associated with troublesome symptoms as well as difficulty of eradication.

The significance of BPH is its hindrance to onset of micturition, slow rate of urine flow, and incomplete bladder emptying. Malignancy in the prostate has become a major type of cancer problem of males in the United States. However, many malignant neoplasms occur at such a late age, or are of such a slow rate of growth, that it is questionable whether intervention will improve life expectancy or even quality of life.

Pharmacotherapies for BPH
Hormonal antagonists. Inhibition of testosterone reduction to DHT by the enzyme 5AR (5-alpha-reductase) through use of finasteride for treatment of BPH has been reported in various clinical studies. There it has shown negative effects on sexual function and minimal levels of therapeutic benefit.

However, a 1995 evaluation reported on effects of sleep-related erections, potency, and libido in 20 healthy, sexually active men, ages 41-64 years, during double-blind, randomized dosing with 5 mg/day finasteride or placebo. Finasteride did not reliably inhibit sleep-related erections or self-reported sexual activity versus placebo. Because it inhibits mainly type 2 5AR activity, whereas type 1 5AR is the major enzyme in the central nervous system, a role of DHT in libido and potency is not excluded.

Information on quality of life and assessment of sexual functioning was derived from trials using bicalutamide, 50 mg/day, for both prostate cancer and BPH. Over 3,000 men, the majority of whom were patients with prostate cancer, received this new oral antiandrogen at once-daily doses ranging from 10 to 200 mg daily, corresponding to a total exposure to the drug of over 1,500 patient years. The most commonly reported adverse events were those to be expected with an antiandrogen (i.e., breast tenderness, gynecomastia, and hot flushes). Only 0.3% of patients in the whole trial program had to be withdrawn because of changes in liver function, and there were no clinically significant changes in mean results of liver function tests.

Alpha-1 adrenergic selective antagonists. Relief of the urinary symptoms of BPH-most notably, difficulty of urine flow from the bladder-has been established for alpha-1 adrenergic receptor antagonists. This is a result of greater relaxation, during urination, of smooth muscle in the prostate about the urethra at the base of the bladder. Doxazosin, terazosin, and tamsulosin are antagonists with approved indications for BPH. Some reports say symptomatic benefit with these agents is superior to that with finasteride.

Herbal remedies. Many direct mail purveyors of herbals offer products for "prostate problems" as a prominent part of their panoply of cure-alls. Amid controversy regarding the relative efficacy of therapy for relief of the symptoms of BPH, a lipid-sterolic extract of Serenoa repens known as permixon has been shown effective in opposing the effects of androgen-receptor activation on cultured human prostatic cell lines.

A six-month, double-blind, randomized equivalence study compared the effects of 320 mg of permixon with those of 5 mg finasteride in 1,098 men with moderate BPH. Both agents lowered symptom score equally, improved quality of life (by 38% and 41%, respectively), and increased peak urinary flow rate ( + 25% and + 30%, respectively).

There was no difference in the percent of responders with a 3-ml/sec improvement. Finasteride markedly reduced prostate volume and serum PSA levels (-41%); permixon improved symptoms despite causing little reduction in volume (-6%) and no change in level of PSA. Permixon rated superior to finasteride in a sexual function questionnaire and evoked fewer complaints of diminished libido and/or impotence. Both relieved symptoms of BPH in about two thirds of patients, but permixon, unlike finasteride, had little effect on androgen-dependent parameters, suggesting that a mechanism besides androgen antagonism may be involved in the symptoms of BPH.
Finasteride and minoxidil in treating baldness
Finasteride inhibits the formation of DHT in some target organs, including the skin and scalp. The pathogenic mechanisms of androgenetic alopecia-hereditary baldness-are thought to depend on elevation of the level of DHT, which interrupts the hair cycle and shortens the growth phase. In some cases, an increase in DHT has been found, seemingly caused by higher activity of 5-alpha-reductase.

Research has tested the response to reductase inhibition by finasteride in both hirsutism and androgenetic alopecia, with success claimed. In men with alopecia, the drug seems to have increased the number of active hair follicles and improved the shape of follicles in the anagen phase; simultaneous decrease of DHT level in the scalp was noted. In two large multicenter trials involving over 1,500 men, a 1-mg oral tablet of finasteride increased hair growth in a majority of the men. The change was measurable by hair counts and was of cosmetic value. This finasteride form and a stronger 5% solution of minoxidil are expected to be marketed within a year.