Is it andropause?

Recognizing androgen deficiency in aging men

Robert S. Tan, MD, MBA; Shou-Jin Pu, MD

VOL 115 / NO 1 / JANUARY 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To become familiar with the physiologic factors involved in androgen decline in older men
• To recognize the limitations of laboratory tests in diagnosis
• To be able to identify the confounding factors that can confuse diagnosis of the andropause syndrome

Dr Tan is a consultant for GlaxoSmithKline, Eli Lilly and Company, and Solvay Pharmaceuticals, Inc. He discloses no unlabeled uses of any product mentioned in this article.

Preview: In primary care practice, it is not unusual to encounter male patients in their 50s or older who report having loss of libido, erectile dysfunction, fatigue, and depression. Such signs and symptoms may signal an age-related decline in androgen levels, which commonly begins after age 40. However, psychologic problems and medical illness often confound the diagnosis. Drs Tan and Pu, who are currently conducting research on androgen deficiency, discuss the diagnostic difficulties of the physiologic phenomenon of andropause and offer a comprehensive approach to clinical assessment and laboratory evaluation.
Tan RS, Pu S-J. Is it andropause? Recognizing androgen deficiency in aging men. Postgrad Med 2004;115(1):62-6

The term andropause refers to a state of lowered androgen levels. Androgens are a group of hormones that include testosterone, dehydroepiandrosterone, and androstenedione, among others. It is a misnomer to classify them as "male hormones" because they are present in both males and females, albeit in different amounts. There is undeniable evidence that aging results in a lowering of androgen levels.

In men between the ages of 40 and 70 years, each year the total testosterone level declines about 1.6%; free testosterone, 2%; and bioavailable testosterone, 2% to 3%. In contrast, the level of sex hormone-binding globulin (SHBG) increases 1.6% per year (1). On the basis of total testosterone measurements, 20% of men older than 55 years are hypogonadal (2,3). However, when bioavailable testosterone levels are measured, 50% of men older than 50 years are defined as hypogonadal (4).

Hypogonadism and the andropause syndrome

Hypogonadism (ie, low testoster-one level) that occurs with aging is the result of both primary gonadal failure and hypothalamic-pituitary failure. Primary hypogonadism involves a decrease in the number of Leydig's cells, reduction of testosterone production, and decreased secretion of testosterone in response to the stimulation of human chorionic gonadotropin. The physiologic factors involved in androgen decline are discussed in the box at the end of this article.

Because the decline in androgens is gradual, the term androgen decline in aging males (ADAM) has been used to describe this phenomenon. Alternatively, partial androgen decline in aging males has also been suggested because the androgen deficiency in older men is generally moderate and not a complete deficiency. Symptomatic hypogonadism is sometimes referred to as the andropause syndrome (13). Knowledge of the patient's history and a thorough physical examination combined with laboratory tests are the keys to an accurate diagnosis of andropause syndrome (14).

Physical manifestations
As in menopause, symptoms may be present or absent in andropause. Transitory symptoms include mood changes (eg, decreases in energy level and feeling of well-being) and changes in sexual function. Potential long-term effects of hypogonadism include osteoporosis, muscle atrophy, and cognitive changes. In our study involving 302 men (most older than 60 years) (14), the dominant symptoms were loss of libido and erectile dysfunction (46%), fatigue (41%), and memory loss (36%). The correlation of symptoms to levels of testosterone is highly variable and is the subject of our ongoing investigation on relative hypogonadism (15).

Laboratory findings
Most laboratories give a normal range of 260 to 1,000 ng/dL (9.02 to 34.7 nmol/L) for total testosterone and 50 to 210 ng/L (174 to 729 pmol/L) for free testosterone (16). Decreased sensitivity to androgens occurs in target organs; thus, absolute serum levels of testosterone can sometimes be misleading. In addition, the range often is not age-adjusted, which poses a dilemma for physicians. Patients may have low-normal levels and yet display symptoms, which are reversed after androgen supplementation. This phenomenon suggests the possibility of "relative hypogonadism," in which normal levels are individualized for each patient (15). Another dilemma is that testosterone levels can vary during the course of a day. Frequent sampling of testosterone in a study of 20 healthy men (17) revealed levels ranging from 105 to 1,316 ng/dL (3.64 to 45.67 nmol/L).

Effects of aging and obesity

Testosterone is produced by fetal testes as early as the first trimester. Levels in adult males peak at about age 20 years and gradually decline thereafter. Total testosterone declines at the rate of 3.82 nmol/L (110 ng/dL) per year, typically after age 40 (18). Levels of bioavailable testosterone decline much more dramatically. Bioavailable testosterone is thought to be the "active" component of androgen acting directly at the cellular level. It consists of free testosterone and that loosely bound to albumin. Binding with SHBG increases with the aging process and hence decreases the available free testosterone (19,20). Overall, the impact of aging on testosterone is negative.

Obesity in men can be accompanied by a significant decrease in testosterone levels. In moderate obesity, total testosterone levels may appear to be low because of the decrease in SHBG binding capacity. Free testosterone, if measured, is usually normal. However, massively obese men have true hypogonadotropic hypogonadism, including decreased free testosterone as well as total testosterone levels (21).

Clinical assessment and screening questionnaires

Careful history taking and physical examination are important in clinical assessment of a patient with hypogonadism. During history taking, the physician should inquire about loss of libido and distinguish it from erectile dysfunction. A loss of early-morning erection can be indicative of hypogonadism. In addition, a history of chronic alcoholism should be ascertained, because alcohol use can suppress the production of androgens.

The presence of various factors may confound diagnosis (table 1). Stress and chronic illness can depress testosterone levels, as can use of such medications as cimetidine (Tagamet), digoxin (Digitek, Lanoxicaps, Lanoxin), and spironolactone (Aldactone). Diabetes, insulin resistance, and obesity also have been linked to hypogonadism (2,9,22). Even anemia can result in fatigue and loss of libido. Therefore, the physician should look for symptoms and signs of anemia, diabetes, and hypothyroidism. Hypogonadism may also result from pituitary tumors and such rare conditions as Prader-Willi syndrome, Klinefelter's syndrome, and Kallmann's syndrome, which should be ruled out in the clinical assessment.

Table 1. Factors that may confound diagnosis of andropause syndrome

Chronic illness (eg, diabetes, chronic renal failure, cirrhosis, anemia) Clinical depression Decrease in albumin from alcohol abuse and poor nutrition Acute stress (eg, surgical operation, severe burn, acute myocardial infarction) Medications (eg, cimetidine [Tagamet], digoxin [Digitek, Lanoxicaps, Lanoxin], spironolactone [Aldactone], antidepressants) Other endocrinopathies (eg, hypothyroidism, Cushing's syndrome) Hypothalamic-pituitary tumor, hemochromatosis Circadian rhythm of testosterone Kallmann's syndrome, Klinefelter's syndrome, Prader-Willi syndrome

Physical examination should include measurement of weight, body mass index, waist-hip ratio, and body fat (23). The skin should be examined for evidence of hyperestrogenism (eg, spider telangiectasia). The face, axilla, and groin should be inspected for hair loss. Testicular size can be measured with an orchidometer. A kyphotic spine may be suggestive of osteoporosis. A prostate examination also should be done as part of the screening.

Screening tools such as the ADAM questionnaire (24) can be helpful for detecting symptoms of androgen deficiency. However, this tool is sensitive but not specific, and it may detect cases of clinical depression or even hypothyroidism. The Geriatric Depression Scale (25) and the Folstein Mini-Mental State Examination (26) can be used to screen for depression and cognitive problems, respectively. Unfortunately, memory loss in andropause can be subtle, and more sophisticated neuropsychologic tools may be needed (27).

Laboratory evaluation

Laboratory assessments should be used only in conjunction with a thorough history and physical examination before the diagnosis of andropause syndrome is made. Reliance on laboratory tests alone sometimes leads to misdiagnosis. Because of aging-related alterations in binding with SHBG, measurement of bioavailable testosterone is the preferred test in patients older than 65 years. Most laboratories do not offer the dialysis equilibrium test, the "gold standard" for free testosterone; rather, they calculate the level according to a formula based on the total testosterone measurement.

Radioimmunoassay remains the most common method for assessing testosterone levels. Saliva testing for testosterone is a novel approach that is convenient for the patient. If saliva testing is done correctly, the results correlate well with free testosterone levels (28). Conservatively, free testosterone levels of less than 50 ng/L (174 pmol/L) or total testosterone levels of less than 260 ng/dL (9.02 nmol/L) with consistent clinical symptoms and signs are diagnostic of androgen deficiency (3,4). The Endocrine Society Andropause Consensus Statement has recommended treatment for patients with the symptom complex and a total testosterone level of less than 200 ng/dL (6.94 nmol/L). If the total testosterone level is more than 400 ng/dL (13.88 nmol/L), it is normal, and clinical judgment should guide the next steps. Although testosterone is secreted in spurts and the levels are highest after awakening, the daily fluctuation in serum testosterone levels is attenuated in older men.

If the initial testosterone level is low, further evaluation should be undertaken to determine whether there are reversible causes of the low testosterone level. Luteinizing hormone (LH) and follicle-stimulating hormone levels also should be measured. Some men in andropause experience a slight rise in LH level. However, the rise is modest compared with the increase that occurs in menopause. Prolactin measurements are useful to screen for rare cases of hypogonadism resulting from prolactinoma. Because there may be overlapping conditions mimicking the andropause syndrome, it would be prudent to measure thyrotropin and cortisol levels, if indicated. Routine laboratory tests (eg, complete blood cell count, measurement of liver enzymes, renal function studies, prostate-specific antigen test) are also indicated.

In elderly patients in whom nutrition may be a problem, measurement of zinc levels may be useful. Zinc has antiaromatase action and can be used to treat hypogonadism (29). A second measurement of serum testosterone should always be obtained to confirm androgen deficiency before testosterone replacement therapy is started. If the initial free or bioavailable testosterone level is within normal range in a patient with symptoms and signs of androgen deficiency, clinical status and testosterone levels should be monitored on follow-up visits (30).

Conclusion

Primary care physicians are probably in the best position to evaluate the andropause syndrome in aging patients. They have knowledge of the multiple factors that can affect testosterone levels. Some factors associated with andropause result from lifestyle habits or stress; therefore, counseling may have a big role in treatment of these patients. Although weight loss may reverse hypogonadism in some obese men, further research is needed in this area. Exercise, particularly weight training, may even increase testosterone levels in older men (31). An overreliance on laboratory assessment of andropause syndrome has resulted in underdiagnosis and, at times, overdiagnosis. Physicians need to be aware that testosterone levels are not static and that they change over time. Listening carefully to the patient is the key to optimal management.

References

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Physiologic factors: Is andropause the "male menopause"? In a healthy man, the testes produce 95% of the androgens, namely testosterone. That amounts to 5 to 10 mg of testosterone daily. The adrenals produce the rest of the androgens, mainly in the form of dehydroepiandrosterone. The pituitary gland secretes luteinizing hormone (LH) and regulates the production of testosterone in Leydig's cells from cholesterol. Follicle-stimulating hormone (FSH) primarily affects spermatogenesis. Testosterone, in turn, is metabolized to dihydrotestosterone (DHT) by 5-alpha-reductase and undergoes aromatization to estradiol by aromatase. DHT is linked to prostate hypertrophy and male alopecia (5). Ninety-eight percent of circulating testosterone is bound to plasma proteins, while the remaining 2% (free testosterone) is responsible for biologic activity. About 40% of the bound testosterone is bound to sex hormone-binding globulin. The rest is weakly bound to albumin and is readily available to tissue when needed. Bioavailable testosterone includes free testosterone and testosterone that is loosely bound to albumin (6). The decline in testosterone levels with aging is associated with an increase in FSH and, to a lesser extent, LH. A low testosterone level with an abnormal LH pulse suggests an age-associated impairment of secretion of hypothalamic gonadotropin-releasing hormone (7,8). Testosterone levels decline gradually in andropause. In contrast, menopause usually has a narrower window of 5 to 10 years. Sperm production in males is primarily regulated by the effect of LH on Leydig's cells in the testes. Testosterone has a supplementary role in regulating spermatogenesis. Fertility in men may not be affected in andropause, although the numbers of sperm with normal motility and morphology may be altered (9). In contrast, menopause ultimately results in shutdown of the ovaries and brings about a cessation of reproductive capability. Long-term deprivation of androgens and estrogens in both men and women leads to similar outcomes: osteoporosis, muscle loss, and cognitive changes. Although the precise mechanism whereby androgens affect bone and cognition is unclear, it has been postulated that the effect is the result of both testosterone itself and the conversion to estradiol (10-12).

Dr Tan is associate professor, geriatrics and men's health programs, department of family practice and community medicine, University of Texas Medical School at Houston, and medical director, Garden Terrace Alzheimer's Center, Houston. Dr Pu is a fellow in geriatric medicine, University of Texas Health Sciences Center, Houston. Correspondence: Robert S. Tan, MD, MBA, Department of Family Practice and Community Medicine, University of Texas Health Sciences Center, 6431 Fannin St, JJL Suite 308, Houston, TX 77030. E-mail: robert.s.tan@uth.tmc.edu.

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