Testosterone production declines with advancing age: 20% of men over age 60 and 30% to 40% of men over age 80 have serum testosterone levels that would be subnormal in their young adult male counterparts. This apparent physiologic decline in circulating androgen levels is compounded in frequency by permanent disorders of the hypothalamic-pituitary-gonadal axis (see below). These include the transient deficiency states associated with acute stressful illness such as surgery, myocardial infarction, and so forth, and the more chronic deficiency states associated with wasting illnesses, such as cancer and acquired immunodeficiency syndrome.

Male factor infertility is probably responsible for one third of the 10% to 15% of couples who are unable to conceive within 1 year of unprotected intercourse. Most of these male-associated cases result from diminished, absent, or faulty spermatogenesis. In addition to abnormal sperm production, other conditions, including obstructive ductal disease, epididymal hostility, immunologic disorders, and erectile/ejaculatory dysfunction should be considered. Finally, since combined female-male infertility is common, and fertility as well as psychological well-being are ultimate goals, both partners must be assessed from the outset.

The physiologic regulation of the hypothalamic-pituitary-gonadal axis is shown in Figure 1. Circulating testosterone is largely protein-bound (the major protein being sex hormone-binding globulin [SHBG]) with only 2% present as the biologically active or free fraction. Some authors believe that the bioavailable fraction (that present in the supernatant after ammonium sulfate precipitation, representing testosterone loosely bound predominantly to serum albumin) is more meaningful. Hepatic SHBG production rises with aging and thyroid hormone excess and declines in hyperinsulinemic states (obesity and type 2 diabetes), so that free testosterone values may not always be concordant with total testosterone values. The biologic effects of testosterone may be mediated directly by testosterone or by its metabolites 5∝-dihydrotestosterone or estradiol (Figure 2).

Male hypogonadism is either due to a primary (hypergonadotropic) testicular disorder or is secondary (hypo-[or normo-] gonadotropic ) to hypothalamic-pituitary dysfunction, as illustrated in Figure 3. Combined disorders also occur. Examples of the major causes of male hypogonadism are shown in Tables 1 and 2.

Puberty
Delayed, arrested, or absent testicular growth and secondary sex-characteristic development are hallmarks of pubertal disorders. Skeletal proportions may be abnormal (eunuchoid) with >5 cm difference between span vs height and between pubis-floor vs pubis-vertex dimensions.

Adult
Manifestations in adults are generally more subtle. Perhaps the minor contribution of adrenal androgens (or androgenic precursors) may substitute for testicular deficiency once the target tissues have been fully developed. Moreover, ingrained behavior patterns may be resistant to androgenic hormone deficiency. Certainly, either prolactin excess and/or testosterone deficiency in men may result in impaired libido and erectile dysfunction. The yield of finding hyperprolactinemia and/or testosterone deficiency in patients presenting with these symptoms is generally considered to be low, usually <5%. However, a recent, large survey of patients with erectile dysfunction presenting to a Veterans Affairs center suggests that the prevalence of these abnormalities is substantial—18.7% of patients with low testosterone and 4.6% with elevated prolactin levels.¹

The first manifestation of hypogonadism may be a consequence of a large space-occupying intra- or parasellar lesion manifested by headaches, bitemporal hemianopia, or extraocular muscle palsy. Galactorrhea as a manifestation of hyperprolactinemia is rare (but rarely sought for). Unexplained osteoporosis or mild anemia sometimes is the clue to an underlying hypogonadal state. Some common clinical conditions associated with male hypogonadism are listed in Table 3. The subject of androgen deficiency and the aging man is dealt with in greater detail below.

If gonadotropin levels are not elevated despite clearly subnormal testosterone values, anterior pituitary (thyroid/adrenal) function should be screened for by obtaining free thyroxine and thyroid-stimulating hormone values as well as an early morning cortisol value. A magnetic resonance image (MRI) of the brain/sella should be considered. An exception to this recommendation is the condition of morbid obesity, in which both total and free testosterone levels are typically low and gonadotropin values not elevated. Hyperprolactinemia, even of a small degree, may also warrant ordering an MRI, since interference of hypothalamic-pituitary vascular flow by space-occupying, stalk-compressing lesions will lead to disruption of the tonic inhibitory influence of hypothalamic dopamine and result in modest hyperprolactinemia (20-50 ng/mL range).

A semen analysis should be obtained when fertility is in question.

Useful criteria for selecting preparations for individual patients are summarized in Table 5.

In addition to monitoring testosterone levels periodically, prostate screening and measurement of hemoglobin and hematocrit levels must also be performed at intervals when the patient is on therapy:²

Prostate Screening
Levels of prostate-specific antigen (PSA) should be checked at 3, 6, and 12 months. If the patient is truly hypogonadal to begin with, expect a significant rise at the 3-month assessment. Thereafter, the usual criteria apply regarding the possible presence of an underlying malignancy (>4 ng/mL, or rate of rise >1.5 ng/mL/2 yr or >2 ng/mL overall). These criteria continue to be revised by our urology colleagues, tending to become more stringent with time. For example, a PSA rise of >1 ng/mL/yr has been suggested as an early warning guide, and closer surveillance has been recommended even at rates of 0.7 to 0.9 ng/mL/yr.² A digirectal examination should be performed at 3 to 6 months and at 1 year after therapy is initiated. An urologic consultation should be obtained if indicated.

Hemoglobin (Hb)/Hematocrit (Hct) levels should be checked periodically. Increments are to be expected in all, but an Hb level >17.5 and/or Hct >55% suggests overtreatment (occasionally abuse). Greater increments tend to occur more frequently with the intramuscular than with the transdermal preparations. If dosage adjustments do not solve the problem, look for another underlying cause.

Contraindications to Therapy
Physicians should take into consideration a number of clinical situations in which absolute or relative contraindications for the use of testosterone exist (Table 6). It should be noted that no long-term studies in large numbers of patients (neither young or old) have been performed, so potential risks/benefits need to be individualized.

Benefits. In genuinely hypogonadal men, testosterone can be expected to result in improvement in a variety of clinical areas (Table 7). Least predictable are the effects on sexual function, cognitive function, and muscle strength.

Risks
Concerns regarding the use of testosterone have been noted in Table 6 and in reference 2. There is no evidence that the incidence of prostate cancer is increased by testosterone replacement. The underlying concern is that it might alter the course of an occult malignancy estimated to be present in more than 50% of men older than age 50. On the other hand, no one would recommend prophylactic castration to prevent prostate cancer, so that, in my view, testosterone replacement in the hypogonadal male should not be avoided. Although there are genuine concerns about worsening of benign prostatic hyperplasia, this may apply only to severe cases with large prostate volumes. Indeed, one study in older men has even suggested improvement in benign prostatic hyperplasia symptoms, although not statistically significant and by an unknown mechanism.³

The Elderly Man
The aging man represents a special case and has been the subject of a recent review.⁴ There is a well-known decline in testosterone production with aging in otherwise healthy men. This decline in mean values can be seen in free testosterone levels beginning in the mid-40s (some authors suggest even earlier) as a consequence of increasing SHBG levels (mechanism not known). Total testosterone levels decline on average beyond age 70. The diurnal rhythm, seen in younger men, is lost beyond age 60.⁵ Although testicular volume also declines in this age group,⁶ spermatogenesis may be well maintained into the 80s or even older. Gonadotropin levels tend to rise after age 70, indicating that the testosterone deficiency is usually primary.⁶ Figure 4 schematically shows these hormonal changes with age.

Using the criterion of a low testosterone value (and remembering that there is considerable variability in commercially available tests regarding normal young-adult ranges), it has been estimated that 7% of 40- to 60-year-olds, 22% of 60- to 80-year-olds, and 36% of 80- to 100-year-olds are hypogonadal.⁷

The ultimate issue as to whether these changes are normal and physiologic or should be considered pathologic, thus demanding therapy, remains unresolved. Indeed, it is a situation analogous to the ongoing dilemma of hormone replacement therapy in postmenopausal women, although in this group the hormonal deficiency state is usually more abrupt and symptomatic.

The scientific basis to help formulate guidelines for dealing with the issue of hormone replacement therapy in men was reviewed in a December 17, 2003, conference by the Institute of Medicine's Committee on Testosterone and Aging.⁸ Many of the potential benefits of therapy (Figure 6) have been realized in small, well-controlled studies of elderly men. Moreover, none of the risks has been proven in a clinical trial. For the present, the Committee did not recommend a large-scale study in order to determine whether the risk for prostate cancer would be increased, since the costs of such a study were deemed to be too prohibitive.

In the meantime, practical guidelines for dealing with hypogonadism in elderly men have been suggested.⁹ I have found the recent overview in the Cleveland Clinic Men's Health Advisor (e-mail address mhealth@palmcoastd.com) to be useful for patients.¹⁰

The American Association of Clinical Endocrinologists has published 2002 updated guidelines for the evaluation and treatment of hypogonadism in adult male patients¹¹. This 18-page review, geared particularly for endocrinologists, expands upon some of the areas reviewed in this chapter and provides a more detailed look into aspects of male infertility.

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2. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350:482-92.
   
   
3. Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab. 1997;82:3793-3796.
   
   
4. Rajfer J, suppl ed. Decreased testosterone in the aging male. Rev Urol. 2003;5(suppl 1):S1-S50.
   
   
5. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56:1278-81.
   
   
6. Stearns EL, MacDonnell JA, Kaufman BJ, et al. Declining testicular function with age. Hormonal and clinical correlates. Am J Med. 1974;57:761-66.
   
   
7. Vermeulen A, Kaufman JM. Ageing of the hypothalamo-pituitary-testicular axis in men. Horm Res. 1995;43:25-28.
   
   
8. Liverman CT, Blazer DG, eds. Testosterone and aging: clinical research directions/Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy, Board on Health Sciences Policy, Institute of Medicine of the National Academies. Washington, DC: National Academies Press, 2004:1-240.
   
   
9. Snyder PJ. Hypogonadism in elderly men-what to do until the evidence comes. N Engl J Med. 2004;350:440-442.
   
   
10. Testosterone: anti-aging jump start? In: Lang RS, ed. Men's Health Advisor. 2003;5:1,7.
    
    
11. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients - 2002 update. Endocr Pract. 2002;8:440-456.

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