Andropause: Clinical Implications of The Decline in Serum Testosterone Levels With Aging in Men

REVIEW ARTICLE
Journal of Gerontology: MEDICAL SCIENCES In the Public Domain

2002, Vol. 57A, No. 2, M76–M99
Andropause: Clinical Implications of the Decline

in Serum Testosterone Levels With Aging in Men
Alvin M. Matsumoto
Department of Medicine, Division of Gerontology and Geriatric Medicine, Population Center for Research in Reproduction,
University of Washington School of Medicine, and Geriatric Research, Education and Clinical Center, Clinical Research Unit,
Downloaded from https://academic.oup.com/biomedgerontology/article/57/2/M76/547924 by guest on 03 July 2023

V.A. Puget Sound Health Care System, Seattle.
I T is now well accepted that serum testosterone (T) levels

decline progressively with aging in men (1–5). This de-
cline is associated with alterations in body composition; di-
PHYSIOLOGICAL BASIS OF ANDROPAUSE
Age-Related Decline in Serum T Levels

minished energy, muscle strength, and physical function; In both cross-sectional (5,6,18–38) and longitudinal stud-
reduced sexual function; depressed mood; and decreased ies (39–42), beginning in the third decade, aging is associ-
cognitive function. Similar changes occur in young men ated with a gradual and progressive decline in serum T lev-
with androgen deficiency and are improved with T replace- els at a rate of approximately 1% per year. As a result,
ment therapy. However, the physiological and clinical sig- 20% of men older than 60 and 50% of men older than
nificance of the aging-associated decline in serum T levels 80 years of age have serum total T levels below the normal
in men is unclear, particularly because T levels may remain range for young men (39,43,44).
within the normal range for young men. From a practical Circulating T is approximately 98% bound to serum pro-
clinical standpoint, it is most appropriate to define “andro- teins, predominantly to sex hormone-binding globulin (SHBG),
pause” as an age-related decline in serum T levels in older the major binding protein for T in blood, and albumin (45–
men to below the normal range in young men that is associ- 47). Only 1% to 2% of T in circulation is completely un-
ated with a clinical syndrome (i.e., symptoms and signs) bound or free. Because T is bound with high affinity (i.e.,
consistent with androgen deficiency. The decline in T levels tightly) to SHBG, SHBG-bound T is not available to most
is a consequence both of aging per se and age-associated co- tissues for action. In contrast, T is bound with low affinity
morbid illnesses and medications that are used to treat them (weakly) to albumin, so both albumin-bound and free T are
(6–13). However, regardless of the etiology, androgen defi- bioavailable to most tissues for action. Because the concen-
ciency may contribute, at least in part, to age-related decre- tration of SHBG increases with aging, serum-free T and
ments in physiological function and may be associated with bioavailable T (free plus albumin-bound T) concentrations
a clinical syndrome. decline more markedly than total T levels with aging (13,
Andropause has also been referred to by some as “androgen 16,20,24,26,27,29,31,33,36,39,41,48). Therefore, a much
deficiency in the aging male (ADAM),” “partial androgen larger percentage of older men have levels of these biologi-
deficiency in the aging male (PADAM),” or “aging-associ- cally active fractions of circulating T below the normal
ated androgen deficiency (AAAD).” The term “male meno- range for young men (39,49).
pause” is inappropriate because there is no interruption or Age-related and other alterations in SHBG have impor-
cessation of menses, and “viropause” is inaccurate because tant practical clinical implications in the diagnosis of andro-
there is no loss of virilization. “Male climacteric” refers to gen deficiency. Because total T assays measure both free T
the syndrome of endocrine, somatic, and psychic changes and T bound to SHBG and albumin, alterations in SHBG
that occur in normal men with aging. This term emphasizes and/or albumin result in changes in total T levels in the
the multidimensional nature of age-related changes, includ- same direction. Measurements of bioavailable or free T are
ing decreases in other hormones such as growth hormone not affected by alterations in SHBG. Therefore, they pro-
(GH), insulin-like growth factor-1 (IGF-1), dehydroepi- vide a better assessment of biologically active T in blood,
androsterone (DHEA), and melatonin (1,14–17), but it does especially in common clinical states such as aging in which
not relate aspects of the male aging syndrome specifically SHBG increases or moderate obesity in which SHBG de-
with androgen levels. The term “andropause” is not com- creases (47,50–52).
pletely accurate because androgen secretion does not cease Because SHBG levels increase with aging, many older
altogether. However, because it is the only term that relates men with low-normal total T levels have free or bioavail-
the syndrome of age-related physiological changes with the able T levels that are below the normal range for young
gradual and progressive decline in T levels that occurs with men. Therefore, measurements of bioavailable or free T us-
aging, andropause will be used in this review. Andropause ing ammonium sulfate precipitation or equilibrium dialysis,
is a term also used commonly by experts in the field and by respectively, or calculated from measurements of total T
lay persons because it retains some analogy to menopause and SHBG are recommended to diagnose androgen defi-
in women. ciency in older men. Unfortunately, these measurements of
M76
CLINICAL IMPLICATIONS OF ANDROPAUSE M77
free and bioavailable T are not usually performed in local the pituitary gland, decrease with aging (83,84). Most of the
laboratories and are only available through commercial ref- decline of inhibin B levels appears to occur by middle age
erence laboratories. Most local laboratories measure free T with stable concentrations from middle to old age.
using a solid-phase direct analog immunoassay kit. Al- In both cross-sectional and longitudinal studies, the de-
though free T measurements using this method correlate cline in serum T levels with aging is associated with a grad-
with those using equilibrium dialysis, values obtained differ ual increase in serum gonadotropins, FSH, and to a lesser
substantially [e.g., by more than an order of magnitude in extent, LH concentrations (19,25,41,85–87). Although go-
women (53)] from those obtained by equilibrium dialysis or nadotropin levels increase with aging, they often remain
calculated from SHBG, and vary directly with alterations in within the wide normal range for younger men. The result-
SHBG levels (52–56). Therefore, free T measurements using hormonal pattern of a low serum T and normal gonado-
ing direct analog immunoassay kits may not provide useful tropin levels suggests concomitant hypothalamic-pituitary

clinical information beyond that of total T levels. They tend dysfunction in conjunction with primary testicular failure in
to underdiagnose older men with androgen deficiency and aging men. Low serum T and normal gonadotropin levels,
overdiagnose androgen deficiency in men with low SHBG consistent with secondary hypogonadism, are found com-
levels (e.g., moderately obese men). Free T levels measured monly during the work-up of older men with symptoms of
using a direct analog immunoassay should not be used androgen deficiency (see below) (88).
in situations where SHBG levels may be altered (e.g., Detailed studies of pulsatile gonadotropin secretion pro-
older men). vide indirect evidence for age-related alterations in pulsatile
GnRH secretion from the hypothalamus. Compared with nor-
Decline in Both Testis Function and Hypothalamic mal men, young hypogonadal men with low serum T levels
GnRH Regulation With Aging demonstrate an increase in LH pulse frequency and am-
The decline in serum T levels with aging is due both to plitude associated with diminished T negative feedback
impaired testis production of T and hypothalamic secretion (89,90). Compared with young men, healthy older men with
of gonadotropin-releasing hormone (GnRH) resulting in in- low serum T levels demonstrate an abnormal LH pulse fre-
adequate stimulation of luteinizing hormone (LH) secretion quency, reduced LH pulse amplitude, and more disorderly
by the pituitary gland. LH secretion, suggesting an age-associated impairment of
Older men demonstrate a decrease in the number of Ley- the hypothalamic GnRH pulse generator (71,91–98). Basal
dig cells (57–59), the cells of the testis that produce T, re- FSH secretion and pulse amplitude increase, but orderly se-
duction in basal T production (60,61), and marked de- cretion of FSH is maintained in older compared with young
creased in T secretion by the testis in response to maximal men (99–101). Older men also demonstrate an attenuated
stimulation by administration of human chorionic gonado- stimulation of gonadotropin secretion induced by naltrex-
tropin (hCG), an LH-like hormone (62–66). The impact of one or naloxone, opioid receptor antagonists, suggesting
reduced T production on circulating T levels is lessened by altered central nervous system (CNS) endogenous opiate
the decrease in metabolic clearance of T that also occurs regulation of GnRH secretion with aging (97,102). The sen-
with aging (35). The normal circadian variation in serum T sitivity of gonadotropin suppression to T negative feedback
levels with peak concentrations in the morning is blunted in is increased (103–105), and gonadotropin responsiveness to
healthy older men compared to young men (65,67–72), sug- androgen deprivation induced by an androgen receptor an-
gesting an alteration in the hypothalamic circadian pace- tagonist (flutamide) or androgen synthesis inhibitor (keto-
maker function. Because of age-related blunting of the nor- conazole) is attenuated in older compared with young men
mal circadian variation in T levels, early morning serum T (106,107).
levels are lower but late afternoon values are more similar Compared with young men, older men demonstrate slightly
in older compared with young men (23). diminished gonadotropin responsiveness to acute GnRH
Function of the seminiferous tubule compartment of the (85,87,108–110) but a normal LH response to chronic pul-
testis also declines with aging. In older compared with young satile GnRH administration (111), suggesting that pituitary
men, spermatogenesis assessed histologically is reduced gonadotropin secretion remains intact with aging. Together,
(58,73,74), but ejaculated sperm concentration is unchanged these findings suggest that aging is associated with impair-
or increased as a result of diminished ejaculatory volume ments in both testis function and hypothalamic GnRH regu-
and frequency (28,75). The number of sperm with normal lation of gonadotropin secretion.
motility and morphology also decreases but in vitro fertiliz-
ing capacity is relatively well preserved in older men Age-Related Alterations in Androgen Action and Active
(28,76). Despite overall well-preserved fertility potential Metabolism of T
(77) and documented instances of paternity in men older Besides the limited studies of T negative feedback men-
than age 90 years, overall fertility rates decline with age tioned previously, a systematic evaluation of age-related
(78,79), largely as a result of diminished sexual activity changes in androgen action in androgen-responsive target
(80). With older paternal age, the risk of inherited autoso- organs has not been performed. Androgen receptor gene ex-
mal dominant diseases increases in offspring (79,81). The pression in the CA1 region of the hippocampus and the
number of Sertoli cells (57,82), seminiferous tubule cells number of androgen receptor binding sites in genital skin
that support spermatogenesis, and serum levels of inhibin B, are decreased in older compared with young men (112–114).
a Sertoli cell peptide product responsible for feedback inhi- Androgen receptor expression and nuclear androgen recep-
bition of follicle-stimulating hormone (FSH) secretion from tor levels in the prostate are unchanged in older men with-
M78 MATSUMOTO
out benign prostatic hyperplasia (BPH) and are similar to Serum markers of peripheral androgen action such as 3
those in young men (115–117). However, prostate androgen alpha-, 17 beta-androstanediol glucuronide (3 alpha-diol G)
receptor expression is reduced, and nuclear androgen recep- decrease markedly with aging, suggesting an overall decline
tor levels are increased in older men with BPH compared in the total circulating androgen pool (24,138,141). Tissue
with young men. concentrations of DHT decrease within the epithelial com-
The length of trinucleotide CAG repeats in the androgen partment and E2 increase within the stromal compartment
receptor gene is variable and is associated with differences of the normal and BPH prostate gland with aging, empha-
in transcriptional activity, with a shorter CAG repeat length sizing the importance of active metabolism of T in androgen
associated with greater androgen receptor activity and pos- target organs and within specific regions of these organs
sibly overall greater androgen action (118). In the Massa- (142–144).
chusetts Male Aging Study (MMAS), serum total and free T

levels were found to be associated with the CAG repeat Age-Related Comorbid Illnesses and Medications
length in the androgen receptor gene (40). Older men with Suppress Serum T Levels Further
lower serum T levels had an androgen receptor genotype In addition to the decline in serum T levels associated
characterized by a shorter CAG repeat length, suggesting with healthy aging, age-related comorbid illnesses (e.g.,
overall greater androgen activity. It is hypothesized that, in chronic renal, liver, or pulmonary disease, malignancy) in-
older men with shorter CAG repeat length, increased andro- crease, and the use of certain medications that are often used
gen action at the level of the hypothalamic-pituitary axis to treat these illnesses (e.g., glucocorticoids and CNS-active
may result in greater feedback suppression of gonadotropin medications) and malnutrition that is often associated with
and, in turn, endogenous T secretion. This may be an intrin- illness suppress serum T levels even further (11,12,51,145–
sic mechanism that underlies the physiological decline in 148). Compared with community-dwelling healthy older men,
serum T levels with aging. A shorter CAG repeat length in old men with significant illnesses, such as cancer or stroke,
the androgen receptor gene also has been associated with an and those in an inpatient rehabilitation unit or nursing home
increased risk and severity of BPH and prostate cancer have substantially lower serum T levels (6–10,21). These
(119–125) and an earlier age at diagnosis and aggressive- sicker old men also have a higher prevalence of T levels be-
ness of prostate carcinoma (126–129). low the normal range for either healthy young (60-90%)
Androgen action is not simply a function of androgen re- or older men (20-30%).
ceptor expression in target tissues and CAG repeat length,
but involves a complex interaction among androgen ligands Age-Related Decline in Adrenal Androgens
such as T, the androgen receptor, and tissue-specific coacti- Serum concentrations of DHEA, a weak adrenal andro-
vators and corepressors with androgen-response elements in gen that is a precursor of T, decline more rapidly and more
specific genes (130,131). Age-related alterations of the lat- profoundly than those of T with aging (149–152). This has
ter and other transcription factors in androgen target tissues been referred to as “adrenopause.” However, the physiolog-
and their effects on androgen action have not been investi- ical significance of circulating DHEA is unclear at this time.
gated. However, the preliminary findings reviewed suggest Preliminary controlled studies of DHEA treatment failed to
that, in addition to circulating T levels, age-associated demonstrate significant clinical effects in older men and
changes in androgen action may play important roles in the conflicting effects on general well being (149,153–157).
alterations of physiological function that occur with normal Therefore, the term andropause is reserved for the age-
aging and in the pathophysiology of age-related pathologies. related decline in T, the major circulating androgen in
T is actively metabolized to the potent estrogen, estradiol blood.
(E2), by the enzyme aromatase, which is located primarily in
adipose tissue, and to 5 alpha-dihydrotestosterone (DHT), a Age-Associated Physiological Changes Consistent With
more potent androgen than T, by the enzymes 5 alpha-reduc- Androgen Deficiency
tase type 1 and 2, which are located predominantly in skin and Aging is associated with a number of changes in physio-
the prostate (132–134). Many of the actions of T are medi- logical functions, many of which are regulated by andro-
ated, at least in part, by its active metabolites, E2 (e.g., gens. Physiological alterations that are associated with the
bone, brain, and lipids) and DHT (e.g., prostate). Despite age-related decline in serum T levels include decreased lean
declining T levels, serum total E2 and DHT levels do not body mass and muscle mass (predominantly in fast twitch
change or decrease only slightly with aging (24,26,34,37, type II muscle fibers) (158–174); reduced muscle strength
38,135–139). This suggests that, with aging, there is a rela- and power (164,175–180); decreased physical function, aer-
tive increase in aromatization of T to E2 (perhaps due to in- obic capacity, and balance (175,181–187); increased risk of
creased adipose tissue mass) and 5 alpha-reduction of T to falls and loss of independent living; increased fat mass dur-
DHT and/or reductions in the metabolic clearance of E2 and ing middle to old age, in particular increased amounts of
DHT. Because serum SHBG levels increase with aging, se- visceral adiposity, which is associated with insulin resis-
rum bioavailable or free E2 and DHT levels would be ex- tance and increased risk of type 2 diabetes mellitus, hyper-
pected to decrease with aging. The physiological signifi- tension, and atherosclerotic vascular disease, followed by
cance of bioavailable E2 and DHT is not clear. However, stable or decreased fat mass in very old age (159,188–193);
recent studies suggest that bioavailable E2 levels decline decreased bone mineral density (BMD) and increased risk
with aging and correlate better than T with bone mineral of osteoporosis and fractures (194–201); decreased skin
density in men (26,137,139,140). thickness and body hair, and poor wound healing (202,203);
diminished vigor, energy, and general well being; irrita- increase in BMD with E2 treatment in a man with aro-
bility and depressed mood (204); decreased sexual func- matase deficiency provide strong support for a vital impor-
tion (reduced libido, sexual activity, and erectile function) tance of E2 in developing and maintaining normal bone
(80,205–208); impaired concentration and cognitive func- mass (322–328). In older men, administration of an aro-
tion (209,210); sleep disturbances and impaired sleep qual- matase inhibitor increases markers of bone resorption, and
ity (211,212); and decreased hematopoiesis (213,214). E2 replacement in these men decreases markers of bone re-
Similar alterations in physiological function occur in sorption, suggesting an important role for T to E2 conver-
younger hypogonadal men with androgen deficiency and T sion in the prevention of bone resorption (329,330). How-
replacement therapy: increases lean body mass, muscle ever, men with androgen resistance caused by androgen
mass, and strength; decreases body fat mass; improves en- receptor gene mutations have reduced BMD, suggesting
ergy, well being, mood, and libido; increases spontaneous that androgens also play an important role in the develop-

erections during sleep (nocturnal penile tumescence) and in- ment and maintenance of bone mineral content in men
duced by sexual thoughts; improves sexual function; and in- (331–333). The specific roles of T and E2 in regulating
creases erythropoiesis and hematocrit (215–268). There- bone turnover were investigated recently in older men with
fore, it is hypothesized that the decline in serum T levels T and E2 deficiency (induced by a GnRH agonist plus an ar-
with aging contributes, at least in part, to these age-related omatase inhibitor) treated with either physiological T or E2
alterations in physiological function, especially in older replacement (334). E2 but not T was found to be dominant
men with serum T levels below the normal range for young in preventing bone resorption, whereas both T and E2 were
men. Although not uniform, most descriptive studies find a found to be important in maintaining bone formation. Be-
correlation between serum T levels and most of these physi- cause E2 is derived from aromatization of T, it is likely that
ological functions, independent of age. the age-related decline in serum E2 levels is related, at least
Some descriptive studies find a positive correlation be- in part, to the reduction in its substrate, T, with aging. Fi-
tween T levels and lean body mass, and muscle mass and nally, low T levels are a risk factor for hip fractures in older
strength in older men (7,139,269), while others do not (269– men (335–337).
272), and most studies (273–277) find an inverse correlation Most descriptive studies also find significant associations
between T and total or abdominal fat mass, suggesting a re- between T levels and aspects of brain function. In a recent
lationship between serum T and age-related alterations in study, an inverse correlation was found between bioavail-
body composition and muscle strength. Furthermore, serum able T and depression score, suggesting a role for T in the
T levels are lower in men with type 2 diabetes mellitus, and regulation of mood (338). The correlation between T levels
low T levels are associated with a higher risk of developing and libido and sexual activity is weak (339–345), and such
type 2 diabetes (278–282). However, many studies investi- an association is not found in some studies (346). This
gating the association of T levels with total or visceral adi- is consistent with the findings that relatively low serum T
posity and diabetes may have been confounded by the use levels are required to sustain sexual interest and desire
of total or free T assays that were affected by SHBG con- (219,347,348). Although androgen deficiency may contrib-
centrations, which are significantly lower in moderately ute to sexual dysfunction, it is rarely the only or major cause
obese men (283,284). of erectile dysfunction in older men. Erectile dysfunction is
Most epidemiological studies find a positive correlation most commonly due to vascular disease, neuropathy, and
between free T levels within the physiological range and medications (88,349,350). T levels are associated with sleep
high-density lipoprotein (HDL) cholesterol levels, and an efficiency and architecture (351) and inversely with
inverse correlation between T concentrations and hyperten- measures of psychosocial stress (352). Finally, a correlation
sion, insulin and glucose levels, prothrombotic factors, ath- between bioavailable T and general or spatial cognitive
erosclerotic vascular disease, and the presence or severity of function has been reported, suggesting a potentially very
coronary artery disease (CAD) (31,285–303). In prospec- important role for T in the maintenance of cognition and
tive studies, no correlation is found between T levels and memory (353–357).
CAD disease incidence (285). No studies have reported an Given the multifactorial nature of age-related physiologi-
association between T and cardiovascular mortality. There- cal alterations (see below), it is not surprising that there is a
fore, epidemiological studies suggest a protective or neutral relatively weak correlation between serum T levels and
rather than an adverse effect of T on heart disease risk. these physiological changes that occur with aging. In fact,
A relatively weak positive correlation is found between recent large epidemiological studies suggest that much of
free, bioavailable, or total T levels and BMD and fracture the age-associated decline in serum T levels is attributable
risk in some studies (137,139,273,304–310), but no correla- to age-related comorbid illnesses, medications, and lifestyle
tion is found in others (140,311–319). In recent studies, a (8,13,358–360).
stronger correlation is found between bioavailable E2 levels
and BMD and fracture risk than between T and these out- Multifactorial Etiology of Age-Related
comes, suggesting that the age-related reduction in bioavail- Physiological Changes
able E2 levels may be a more important determinant of bone It would be naïve to assume that age-associated androgen
loss with aging in men than T levels (139,140,306,308,311, deficiency is the only cause of the physiological changes
318,320,321). The findings of severe osteoporosis in men that occur with aging. As is the case for many geriatric syn-
with estrogen resistance or deficiency caused by estrogen dromes, the etiology of most age-related alterations in phys-
receptor or aromatase gene mutations, respectively, and an iological function is multifactorial, and many of the factors
M80 MATSUMOTO
extending throughout the life span of an individual, not just

from young adulthood to old age. Finally, it is important to
recognize the essential contribution of falls and trauma to
the major clinical consequence of decreased bone mass and
abnormal bone architecture, fracture, which may lead to
pain, deformity, need for surgery, and associated complica-
tions (e.g., deconditioning or pneumonia), and loss of func-
tion and independent living.
Interactions among the potential etiological factors that
contribute to age-related physiological decline increase the
clinical complexity and highlight the importance of using a

multifactorial approach in managing older patients. For ex-
ample, low serum T levels may contribute to reductions in
E2, GH, and IGF-1 levels (362), decreased exercise or inac-
tivity as a result of weakness and/or poor motivation, and
increased risk of falls related to muscle weakness and poor
balance. T treatment may increase BMD indirectly by in-
creasing E2, GH, and IGF-1 levels and physical activity,
and reducing the likelihood of falls by improving muscle
strength, balance, and spatial cognition. Conversely, many
of the factors that decrease BMD (e.g., poor nutrition, medi-
cations, comorbid illnesses, and excessive alcohol intake)
also may contribute to the reduction in serum T levels. Cor-
rection of poor nutrition, discontinuation of certain medica-
tions such as glucocorticoids, treatment of comorbid ill-
nesses, and discontinuation of alcohol abuse may increase
serum T levels and obviate the need for T treatment. In the
Figure 1. Schematic diagram of the multiple factors that may con- clinical approach to older men with low serum T levels, a
tribute to decreased bone mass and abnormal bone architecture in
older men. These include low free or bioavailable T and E2 levels, similar multifactorial evaluation of possible etiological fac-
low growth hormone (GH) and insulin-like growth factor-1 (IGF-1) tors contributing to other age-related physiological alter-
concentrations, reduced calcium intake, vitamin D deficiency, malnu- ations should be adopted.
trition, use of medications that reduce bone mass (e.g., glucocorti-
coids, or anticonvulsants), decreased exercise or activity, immobility
(e.g., from severe arthritis), lifestyle (excessive alcohol use or tobacco
Potential Consequences and Importance of
smoking), illnesses that reduce bone mass (e.g., primary or secondary Age-Associated Physiological Changes
hyperparathyroidism or multiple myeloma), and genetic factors that Age-associated changes in physiological function have
influence bone metabolism. Reduced bone mass and abnormal bone important potential consequences, including reduced physi-
architecture predispose to fracture following falls or trauma, and cal function, endurance, and activity; increased risk of dis-
fractures may cause significant clinical morbidity and mortality [e.g.,
pain, deformity, need for surgery, complications (e.g., deconditioning ease (e.g. coronary heart disease, diabetes mellitus, os-
or pneumonia), and loss of function and independence]. teoporosis); diminished quality of life; impaired balance
and increased risk of falls; impaired ability to regain func-
tion after an acute illness; and, most importantly, increased
susceptibility to frailty (2,363). In turn, frailty may lead to a
that contribute to physiological decline are modifiable or loss of independence, chronic disability, and a need for as-
treatable. Therefore, optimal clinical management of these sisted living or long-term care; severe psychological and so-
changes requires careful attention to all potential etiological cioeconomic sequelae; and an increase in mortality.
factors. For example (Figure 1), in addition to low T levels, A major clinical focus of geriatric medicine is the preven-
the age-related decrease in BMD and abnormalities in bone tion of frailty. A multifaceted approach is employed to pre-
architecture may be due to low E2 concentrations; low GH vent frailty in elderly persons. This includes interventions to
and IGF-1 levels; inadequate calcium intake; vitamin D de- prevent acute and chronic diseases (e.g., influenza vaccina-
ficiency; poor nutrition; use of medications (e.g., glucocor- tion, smoking cessation); prevent falls and injury (e.g., dis-
ticoids or anticonvulsants); lack of exercise or inactivity due continuation of medications that predispose to falls and hip
to weakness or immobilization (e.g., as a result of severe os- protectors); adequately treat acute and chronic diseases;
teoarthritis); lifestyle (excessive alcohol intake, smoking); identify and treat conditions that impede recovery of func-
age-related illness (e.g., primary and secondary hyper- tion (e.g., delirium and depression); improve physical con-
parathyroidism, multiple myeloma); predisposing genetic ditioning (e.g., aerobic and resistance exercise); improve
background; and/or low peak bone mass during puberty and nutritional intake; and replace hormonal loss (e.g., estrogen
young adulthood as a result of prolonged illness, medica- replacement therapy in postmenopausal women). With re-
tions, or delayed puberty (361). The latter two potential eti- gard to the more gradual and less profound age-related de-
ologies emphasize the need for geriatricians and gerontolo- cline in serum T levels, major unanswered clinical questions
gists to consider aging as starting from conception and are whether T replacement therapy of older men will im-
prove functional status, prevent disease, increase the quality cancer is the most common malignancy in men, and many
of life, and, most importantly, reduce the risk of frailty older men harbor microscopic foci of prostate cancer that do
(2,364). not become clinically apparent during their lifetime (367).
In most (368–370) but not all (371) epidemiological studies,
POTENTIAL BENEFITS AND RISKS OF T REPLACEMENT serum T levels were not associated with a risk of prostate
THERAPY IN OLDER MEN cancer. However, because prostate cancer growth is initially
When considering T replacement therapy in older men, androgen-dependent, there is concern that T treatment of
the potential benefits of T treatment must be weighed older men will stimulate growth of preexisting subclinical
against the possible risks (365). The potential benefits and (microscopic) prostate cancer to become clinically detect-
risks of T replacement therapy in older men (Table 1) are able. This concern is heightened by reports that find a high
based mostly on the clinical studies of the effects of T re- prevalence of prostate cancer (25%) on surveillance biop-

placement in severely androgen-deficient, young, hypogo- sies of older men with low serum T, and normal prostate-
nadal men (discussed in the previous section) and a small specific antigen (PSA) levels and digital rectal examina-
number of controlled trials of T treatment in older men (dis- tions (372,373). However, biopsies were not performed in
cussed in the following section). an age-matched control group of men with normal T levels
Potential benefits of T replacement therapy in older men in these studies, and in other studies, the prevalence of pros-
include increased lean body mass; decreased fat mass and tate cancer in older men with normal PSA levels and digital
visceral adiposity, and reduced risk of diabetes mellitus; in- rectal examinations is comparable to those found in these
creased muscle mass and strength; increased BMD and re- reports (374). As a consequence of more intensive monitor-
duced risk of osteoporosis and fractures; increased body ing of digital rectal examinations and PSA levels, another
hair and skin thickness, and improved wound healing; im- underappreciated potential risk of T treatment in older men
proved physical function, aerobic capacity, and balance; im- is the increased likelihood of detecting subclinical localized
proved libido and sexual function; improved feeling of well prostate cancer for which treatment is unclear. Even if sub-
being and improved energy; reduced irritability and de- clinical disease discovered on biopsy does not affect overall
pressed mood; improved concentration and cognitive func- prognosis, the potential medical, surgical, psychological,
tion; improved sleep quality; increased hematopoiesis and socioeconomic, legal, and ethical consequences of a diagno-
hematocrit; and decreased risk of CAD. sis of subclinical prostate disease may be quite great.
Short-term risks of T administration in older men include Benign prostate growth is also androgen-dependent
stimulation of erythropoiesis, resulting in excessive erythro- (375,376). At the time of puberty, prostate size increases in
cytosis and, if severe, increased blood viscosity and risk of response to the increases in endogenous T production. Pa-
thrombotic complications (e.g., stroke and myocardial in- tients with severe prepubertal androgen deficiency have
farction); induction or worsening of obstructive sleep ap- small, underdeveloped prostate glands, and if left untreated,
nea; worsening of peripheral edema; and development of these men do not develop BPH. Long-term T treatment of
gynecomastia. young hypogonadal men increases prostate size to vol-
The most concerning long-term potential risk of T admin- umes that are comparable to age-matched eugonadal men
istration in older men is the stimulation of previously unrec- (377,378). In men with BPH, treatment with a 5 alpha-
ognized local or metastatic prostate cancer (366). Prostate reductase inhibitor (e.g., finasteride, which inhibits the con-
version of T to the potent androgen DHT) decreases pros-
tate size, improves urine flow, reduces symptoms of BPH,
Table 1. Testosterone Treatment in Older Men: Potential Benefits and decreases the need for BPH-related surgery (379).
and Risks Therefore, another potential long-term risk and concern of T
treatment in older men is the stimulation of BPH growth
Potential Benefits Potential Risks
and worsening of symptoms, urine flow, and urinary reten-
Improve body composition Erythrocytosis, hyperviscosity tion that may require invasive intervention, such as a tran-
↑ Lean body mass Induce or worsen sleep apnea surethral resection of the prostate (TURP).
↓ Fat mass, ↓ visceral fat Worsen edema
Although rarely an issue, T replacement may suppress al-
↑ Muscle mass and strength Gynecomastia
↑ BMD, ↓ fractures Clinical prostate disease
ready compromised sperm production in older men and po-
↑ Hair, skin thickness Worsen BPH requiring intervention tentially reduce fertility. Men have a higher risk of CAD
↑ Physical function Hasten clinical prostate cancer than women. Also, treatment of severely androgen-defi-
Improve brain function Suppress sperm production cient, young, hypogonadal men with physiological T dos-
↑ Libido, sexual function Increase cardiovascular risk ages and eugonadal men with supraphysiological T dosages
↑ Well being, energy decreases HDL cholesterol levels, producing a more athero-
↓ Irritability, depression
↑ Cognitive function
genic profile (286,380–385). Therefore, there is concern by
↑ Sleep quality some that T replacement in older men may increase the risk
Increase hematocrit of cardiovascular disease. As discussed previously, most
Decrease cardiovascular risk epidemiological studies suggest that low T levels are associ-
Notes: ↑ Signifies a potential increase or improvement in the endpoint with
ated with an increase in the prevalence and severity of CAD
testosterone treatment. ↓ Signifies a potential decrease or reduction in the end- in men. However, in the absence of long-term studies to
point with testosterone treatment. BMD bone mineral density; BPH benign evaluate the effects of T on major cardiovascular outcomes
prostatic hyperplasia. such as coronary death, myocardial infarction, and stroke,
M82 MATSUMOTO
the possibility remains that T therapy in older men may in- mildly androgen-deficient older men to those found in stud-
crease cardiovascular disease risk. ies of more severely T-deficient young men.
CLINICAL TRIALS OF T THERAPY IN OLDER MEN Beneficial Effects of T Therapy in Studies of Older Men
Relatively few randomized controlled studies have been In most controlled trials of older men, T treatment re-
reported that investigate the effects of T treatment in older sulted in improvements in body composition. In both con-
men (386–423). In these studies, a variety of T formulations trolled (388,390,401,405,406,415,417,418,424) and uncon-
and dosages were used to treat a relatively small number of trolled (425) studies, the most consistent effects of T
mostly healthy older men, and differing methods were used therapy in older men were an increase in lean body mass
to assess outcomes. However, these preliminary controlled and/or a decrease in total fat mass. One study found a de-
studies suggest that T treatment in older men has beneficial crease in visceral fat mass and improvement in insulin sen-

effects on body composition (increase in lean body mass sitivity with T treatment (406). The effects of T supplemen-
and decrease in fat mass), bone mineral density, LDL cho- tation in older men on muscle strength were more variable.
lesterol, angina and exercise-induced cardiac ischemia, and Some studies found an increase in upper extremity grip
possibly on muscle strength, sexual function, general well strength (408,415,424), and one uncontrolled study found
being, and aspects of cognitive function (Table 2). an increase on lower extremity strength with T therapy
No formal evaluation of the dose-response effects of T (425). However, other carefully performed controlled stud-
treatment on relevant outcomes has been performed in older ies found no increase in either upper or lower extremity
compared to young, androgen-deficient men. Therefore, the strength with T treatment of older men (388,391,394,405,
impression that the effects of T treatment are attenuated in 417,418). The lack of consistent effects of T therapy on
older men relative to young men is not supported by evi- muscle strength may be due to differences in the methods
dence. Also, most studies have been performed on relatively used to assess strength and the dosages and duration of T
healthy older men with T levels in the lower part of the nor- that were administered. In a preliminary report, timed walk-
mal range or slightly below normal. Therefore, it is difficult ing and stair climbing improved in older men with short-
to compare the effects of T therapy in these studies of term T administration (391). Self-assessment of physical
function was maintained in older men treated with transder-
mal T compared to placebo for 3 years (417). Supraphysio-
logical but not physiological T administration also has been
reported to increase the secretion of another anabolic hor-
Table 2. Testosterone Treatment of Older Men: Summary of mone, GH, in older but not young men (398). No controlled
Controlled Studies studies have investigated systematically the effect of T ther-
Benefits Risks apy in older men on muscle power, balance, or endurance,
which together with strength play important roles in the
↑ Lean body mass ↑ Hematocrit, risk of erythrocytosis
↓ Fat mass Sleep apnea
maintenance of physical function in older men.
↑/ Grip and leg strength Clinical prostate disease Controlled studies in which T was administered for at
↑ BMD (if low T initially) BPH symptoms, size, least 1 year demonstrated an increase in lumbar spine and
? ↓ Fractures urine flow hip BMD and prevention of bone loss in the femoral neck
↑/ Sexual function, well being ↑/ PSA (4 ng/ml) with T compared to placebo treatment in older men with
↑ Libido ? ↑ BPH intervention low T levels (388,405,424). In one study, T prevented loss
Erectile dysfunction ? ↑ Clinical prostate cancer
of BMD in the femoral neck despite calcium and vitamin D
↑ Well being, ? ↓ depression HDL cholesterol
↑/ Cognitive function ? ↑ Cardiovascular events
supplementation in all subjects (405). In another study that
↑ Spatial, working memory included older men with normal serum T levels and in
↑ Verbal memory which some but not all subjects received calcium and vita-
Visual memory min D (if dietary intake was inadequate), both T- and pla-
? Slow dementia onset cebo-treated men exhibited an increase in BMD without a
↓ Total and LDL cholesterol significant difference in response between the two groups
↓ Angina and exercise ischemia
?↓ Cardiovascular events
(416). However, further analysis revealed that T treatment
? ↑ Physical function increased BMD in older men who had low serum T levels
? ↓ Frailty (300 ng/dl) at baseline, suggesting that a beneficial effect
? ↑ Quality of life of T treatment on BMD may occur only in older men with
Notes: Composite of benefits and risks of testosterone treament in older men
androgen deficiency. These studies emphasize the impor-
derived from references (385–422). ↑ Signifies that most controlled studies tance of considering other etiologies besides low T levels
found an increase in the endpoint with testosterone treatment. ↓ Signifies that that may contribute to clinical manifestations consistent
most controlled studies found a decrease in the endpoint with testosterone treat- with androgen deficiency in older men (e.g., low calcium
ment. Signifies that most controlled studies found no change in the endpoint intake and vitamin D deficiency in older men with low
with testosterone treatment. ↑/ Signifies that some controlled studies found an BMD) (426). No controlled studies have evaluated the ef-
increase and others found no change in the endpoint with testosterone treatment.
? Signifies that controlled studies have not been performed to address the end-
fect of T on bone architecture or the risk of falls that to-
point sufficiently. BMD bone mineral density; LDL low-density lipopro- gether with BMD contribute to the age-related increase in
tein; BPH benign prostatic hyperplasia; PSA prostate-specific antigen; the risk of fractures in men. Furthermore, no studies have
HDL high-density lipoprotein. investigated sufficient numbers of older men for long
enough (i.e., had sufficient statistical power) to determine strength and physical function, and reduction in hospitaliza-
whether T treatment decreases the incidence of fractures in tion and rehabilitation duration were probably not observed
older men. in this study because the subjects studied were healthy, in-
T treatment in older men increased libido and sexual ac- dependently living, older men who were functioning at a
tivity and improved energy and well being in some con- relatively high level prior to surgery.
trolled studies (400,406,410,413,418,419) but not in others Except for the limited studies mentioned, the effects of T
(388,389,403,404,408,415,417). An uncontrolled trial also replacement on physical function, health-related quality of
reported improvements in energy, mood, well being, libido, life, and the prevention of frailty have not been investigated
and sexual activity (427). One controlled study found no ef- fully in older men. The prevention of frailty is an important
fect of T therapy on clinical depression in older men (415). potential goal of T treatment in older men. The frail older
Other studies have not investigated the effect of T on de- population is at high risk for disability, loss of indepen-

pression in older men. In a recent small, double-blind, ran- dence, and long-term care, and they utilize a major propor-
domized, placebo-controlled study of depressed hypogo- tion of health care resources and dollars. Compared with
nadal middle-aged men, short-term T administration (6 healthy older men, frail older men have lower serum T lev-
weeks) improved sexual function but did not improve de- els and may derive more functional benefit from T treat-
pression scores compared to placebo (266). In preliminary ment.
placebo-controlled studies, certain domains of cognitive
function, specifically spatial, verbal, and working memory, Adverse Effects of T Replacement in Studies of
improved with T treatment in older men (392,403,404) but Older Men
had no effect on general memory, recall, or verbal fluency In controlled studies of up to 3 years in duration, T ther-
(415). In one preliminary study, very short-term T adminis- apy in older men has been tolerated very well. The only ad-
tration (5 days) prevented the improvement in verbal flu- verse effect that has been found consistently in controlled
ency observed in placebo-treated older men (423). Studies trials of T treatment in older men is stimulation of excessive
have not investigated whether T treatment will slow the on- erythrocytosis. However, a major caveat is that studies have
set of clinical dementia in older men. been powered insufficiently to evaluate the long-term risks
Most controlled studies of T therapy in older men found a of T therapy on prostate and cardiovascular disease, and
decrease in total and low-density lipoprotein (LDL) choles- therefore these potential risks remain unknown.
terol with no significant effect on high-density lipoprotein Stimulation of erythropoiesis and an increase in hemat-
(HDL) cholesterol (393,406,408,415,418,420,424). T treat- ocrit of 3% to 5% over baseline has been found in most con-
ment inhibited triglyceride uptake and lipoprotein lipase ac- trolled trials of T treatment in older men. The development
tivity in abdominal but not femoral subcutaneous adipose of erythrocytosis (hematocrit over 51%) during T therapy
tissue depots (407). In several small, randomized, placebo- has been reported in 6% to 25% of older men (394,395,
controlled studies of middle-aged to older men with coro- 399,402,415,416,418). Erythrocytosis has occurred in older
nary heart disease, chronic T treatment decreased angina men with both parenteral and transdermal T administration,
and exercise-induced cardiac ischemia (i.e., increased the but it has been less common with the latter (397,405). This
time to ST segment depression during exercise testing) may be related to the supraphysiological T levels that are
(397,402,414,428). Also, acute intravenous administration produced during the first few days following T ester injections
of T during cardiac catheterization was shown to improve and overall higher mean serum T concentrations compared
exercise-induced ischemia in older men with CAD, proba- with the more physiological T levels that are produced with
bly by inducing coronary artery vasodilation (411,412, the use of T patches or gel. An excessive increase in hemat-
421,422). Subjects with angina also reported significant im- ocrit of more than 55% to 60% results in a substantial in-
provements in quality of life, especially in pain perception crease in blood viscosity and, if untreated, may result in sig-
and limitation resulting from physical problems (397). nificant hyperviscosity and an increased risk of thrombotic
Therefore, in contrast to the general perception that andro- complications. The latter, more serious complications of ex-
gens are bad for the heart, T administration may have bene- cessive erythrocytosis have not been observed in T treat-
ficial effects in older men with cardiovascular disease. No ment trials in older men.
clinical trials have studied sufficient numbers of men for Although T administration has been reported to induce or
long enough periods of time to evaluate the effects of T re- worsen obstructive sleep apnea syndrome in younger hy-
placement in older men on major cardiovascular events, pogonadal men (429,430), this complication has not been
such as cardiac death, myocardial infarction, or stroke. reported in clinical trials of T therapy in older men (416).
In a recent small controlled study, T treatment improved Obstructive sleep apnea may be associated with low serum
physical functional status, grip strength, and mood com- T concentrations (431,432). Therefore, older men with risk
pared to placebo in a small number of relatively frail older factors (e.g., obesity) or symptoms of obstructive sleep ap-
men undergoing rehabilitation on a Geriatric Evaluation and nea (e.g., daytime somnolence and snoring) should be eval-
Management unit (387). In older men undergoing elective uated for symptoms of sleep apnea prior to institution of T
knee or hip arthroplasty, serum T levels were suppressed sig- treatment and should be monitored for this potentially seri-
nificantly postoperatively in men treated with placebo, and ous risk during therapy. Validated instruments, such as the
perioperative supraphysiological T administration tended to Berlin Questionnaire or Epworth Sleepiness Scale, may be
improve postoperative strength, physical function, and he- used for screening and monitoring (433–436).
matocrit (386). More significant improvements in muscle The most worrisome potential risk of T replacement ther-
M84 MATSUMOTO
apy in older men is the induction of clinical prostate disease. available T levels below the normal range for younger men.
Most (368,369,437) but not all (371,438,439) descriptive A rational approach to the diagnosis of androgen deficiency
studies have failed to find a significant relationship between in older men is outlined in Figure 2 and is discussed in the
endogenous T levels and the development of BPH or pros- following sections.
tate cancer. In controlled trials, there has been no significant
increase in prostate size, worsening of BPH symptoms, or The Clinical Syndrome of Androgen Deficiency in
reduction in urine flow rate in T-treated compared with pla- Older Men
cebo-treated older men (386,388,399,400,405,406,415,416, In order to define a clinical syndrome associated with low
418). In some trials of T therapy in older men, serum PSA T and to identify older men at high risk for low serum T lev-
levels increased slightly, mostly within the normal range els, two screening instruments were developed recently.
(below 4 ng/ml) (392,405,408,416,418), but in most studies, The ADAM questionnaire is a symptom-based instrument

PSA did not change significantly during T treatment. No in- that identifies older men with symptoms of low T, with 88%
crease in the need for invasive or surgical therapy for BPH sensitivity and 60% specificity (49). Symptoms associated
or incidence of clinically apparent prostate cancer has been with low serum T levels in this questionnaire are reduced li-
reported. However, the total number of men treated with T bido; lack of energy; decreased strength and/or endurance;
and length of exposure have been limited, and studies have loss of height; decreased enjoyment of life; feeling sad and/
not had the statistical power to evaluate the long-term risks or grumpy; reduced strength of erections; decreased ability
of clinical BPH and prostate cancer in older men treated to play sports; falling asleep after dinner; and reduced work
with T. performance. This symptom complex is similar to that re-
In contrast to the suppression of HDL cholesterol that oc- ported by others for the androgen deficiency in older men
curs with T replacement in younger men with severe hypo- (440–443). The MMAS questionnaire is an epidemiology-
gonadism and supraphysiological T administration in young derived instrument that identifies risk factors for low T lev-
eugonadal men (286,380–385), most controlled trials of T els in older men, with 75% sensitivity and 50% specificity
treatment in older men have not found a significant decrease (444). Risk factors that are associated with low total T lev-
in HDL cholesterol (393,406,415,418,420). As mentioned els include age of 60 years or older; treated diabetes melli-
previously, total and LDL cholesterol decreased in most tus; treated asthma (a surrogate for glucocorticoid use);
studies (393,406,418,420) and were unchanged in the re- sleeplessness (5 hours); nonsmoking; headaches in the
maining trials (394,415) during T therapy of older men. As past 2 weeks (a surrogate for stress); low dominance (dis-
with prostate disease, clinical trials have not investigated like of a directing role); and body mass index (BMI) 27–30
the long-term cardiovascular risk of T replacement treat- or 30.
ment in older men. They have not had sufficient statistical A combination of symptoms and risk factors may better
power to determine whether T treatment affects the rates of identify individuals with low T levels. Therefore, a compos-
major cardiovascular events such as coronary death, myo- ite of the most prominent clinical manifestations of andro-
cardial infarction, and stroke. gen deficiency in older men is presented in Table 3. Symp-
Other known adverse effects of T therapy in younger hy- toms of androgen deficiency in older men include decreased
pogonadal men, such as development or worsening of muscle strength and/or endurance; diminished work and/or
edema, especially in men with underlying edematous states athletic performance; loss of height; history of nontraumatic
(e.g., congestive heart failure, hepatic cirrhosis, nephrotic fracture; decreased pubic and axillary hair; reduced physical
syndrome, and renal failure), gynecomastia, especially in function; diminished sexual interest and desire; decreased
moderate obese men, and suppression of spermatogenesis strength and adequacy of erections; fatigue, tiredness, and
have not been reported in clinical trials of older men. lack of energy; irritability; depressed mood; decreased gen-
eral well-being and enjoyment of life; sleep disturbance;
APPROACH TO THE DIAGNOSIS OF ANDROGEN DEFICIENCY sweats; and hot flushes. Signs include decreased muscle
IN OLDER MEN mass and strength; increased visceral adiposity; low BMD
Although an increasing proportion of men exhibit low se- [osteoporosis or BMD 2.5 SD below that of young men
rum T levels with increasing age, a substantial number of (T-score 2.5) or osteopenia (T-score 1 to 2.5)]; ver-
older men maintain T levels within the normal range. These tebral and/or hip fracture; decreased pubic and axillary hair;
individuals may exhibit clinical manifestations consistent depressed mood; decreased testis size; gynecomastia; and a
with androgen deficiency. It may be argued that they have normocytic, normochromic anemia.
relative androgen deficiency (i.e., a significant age-related
decline in T levels within the wide normal range) contribut- Repeated Low Serum T Levels in the Absence of
ing to their clinical manifestations. However, the clinical Reversible or Remediable Causes
manifestations of androgen deficiency are not specific and If clinical manifestations suggest androgen deficiency, an
are usually multifactorial in nature, and there is no evidence early morning (e.g., 8 AM) T level should be measured to
that these men would benefit from T therapy. Furthermore, confirm low serum T levels. In order to avoid the confound-
the clinical significance of slightly low serum T levels in the ing effects of alterations in SHBG levels on total T, a free or
absence of clinical manifestations consistent with androgen bioavailable T level by equilibrium dialysis or ammonium
deficiency is not clear. Therefore, the diagnosis of andro- sulfate, respectively, is recommended for confirmation of
pause requires both the presence of clinical manifestations androgen deficiency in older men (52,445,446). Alterna-
or a clinical syndrome, and confirmed serum-free or bio- tively, free or bioavailable T levels may be calculated from

Figure 2. Approach to the diagnosis and treatment of androgen deficiency in older men. Diagnostic evaluation for androgen deficiency in
older men should be instituted only in individuals with symptoms and signs consistent with androgen deficiency. Initially, androgen deficiency
should be confirmed with the measurement of a morning serum-free or bioavailable T level. Individuals with an initially low free or bioavailable
T level should be evaluated for remediable causes of androgen deficiency (e.g., illness, medications, or malnutrition) and have serum T levels re-
peated in conjunction with gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) levels. Men who demonstrate sec-
ondary hypogonadism (low T and normal to low gonadotropin levels) should have measurements of serum prolactin and iron to rule out hyper-
prolactinemia and hemochromatosis. Imaging of the hypothalamus and pituitary to rule out a tumor or destructive lesion should be reserved for
men with very low T and low gonadotropin levels, and/or those with markedly elevated prolactin levels (e.g., 100 ng/ml). T replacement ther-
apy should be considered in men with clinical manifestations of androgen deficiency and repeatedly low serum T levels after appropriate correc-
tion or treatment of remediable causes, and if the clinician and patient feel that the potential benefits of treatment outweigh the potential risks,
and there are no contraindications. BMD bone mineral density; MRI/CT magnetic resonance imaging/computed tomography; BPH be-
nign prostatic hyperplasia.
total T and SHBG measurements; calculated values are In younger hypogonadal men, T levels below the normal
comparable to those measured by equilibrium dialysis and range are usually associated with symptoms of androgen de-
ammonium sulfate precipitation methods (52). ficiency. Therefore, the normal range in younger men is
Because total T assays and free T by direct analog immu- used as the reference range for older men as well. This ap-
noassay vary with alterations in SHBG levels, they are not proach is analogous to that used for the interpretation of
recommended (52,53,55,56,446). However, these assays are BMD where values are compared to those in younger men
usually the only ones that are currently available in local (T-score or SD from young controls) and are used to define
clinical laboratories. If total T or free T using direct analog a clinically significant BMD that is associated with an
immunoassay method is used initially to evaluate older men increased risk of fracture (e.g., osteoporosis defined as a
with clinical manifestations of androgen deficiency, values T-score 2.5).
that are in the low-normal to moderately low range (e.g., to- If the initial serum T level is low, evaluation of underly-
tal T of 350–200 ng/dl) should be confirmed with a free or ing acute and chronic illnesses, medications, and nutritional
bioavailable T level measured using a more accurate state should be undertaken to determine whether there are
method. Unless SHBG levels are very low (e.g., nephrotic reversible or remediable causes of low T levels. In these in-
syndrome), total T levels 200 ng/dl in the presence of con- stances, T level should be repeated after the stress of a cur-
sistent clinical manifestations are usually diagnostic of an- rent or recent illness is resolved, medications that may
drogen deficiency. lower T (e.g., glucocorticoids or CNS-active drugs) are dis-
M86 MATSUMOTO
Table 3. Androgen Deficiency in Older Men: sociated with elevated gonadotropin levels, T replacement
Clinical Manifestations treatment should be considered. If the repeat serum-free or
Symptoms Signs
bioavailable T and gonadotropin levels are within the nor-
mal range, the patient’s clinical status should be monitored
↓ Muscle strength and/or endurance ↓ Muscle mass and strength together with serum T levels.
↓ Work and/or athletic performance ↑ Visceral adiposity
Loss of height, history of fractures Low BMD (osteoporosis)
↓ Pubic and axillary hair Vertebral and/or hip fracture Consideration of T Treatment in Older Men With
↓ Physical function ↓ Pubic and axillary hair Repeatedly Low T Levels
↓ Sexual interest and desire Depressed mood The state of knowledge regarding the benefits and risks
↓ Strength of erections ↓ Testis size of T treatment in older men is based on a limited number of
Fatigue, tiredness, lack of energy Gynecomastia short-term controlled studies (3,449–453). No controlled

Irritability, depressed mood Normocytic, normochromic anemia
studies have evaluated the long-term benefits and risks of T
↓ Well-being, enjoyment of life
Sleep disturbances
therapy in older men. Therefore, there are insufficient data
Sweats, hot flushes to formulate firm evidence-based clinical guidelines and
general recommendations for T therapy in older men. Rou-
Notes: Composite of symptoms and signs from references (49,438–442).
tine treatment of older men cannot be recommended at this
BMD bone mineral density.
time. After a thorough assessment and discussion of poten-
tial benefits and risks of T therapy, individual practitioners
must rely on sound clinical judgment and informed patient
preferences before deciding to recommend and prescribe T
continued, and nutritional compromise (e.g., associated treatment for older men with clinical manifestations consis-
with illness) is corrected. tent with androgen deficiency and repeatedly low serum T
If no correctable cause of androgen deficiency is found, a levels.
T level should be repeated together with serum gonadotro- As outlined in Figure 2, T therapy should be considered
pin (LH and FSH) levels. There are significant biological only in older men with clinical manifestations of androgen
and methodological variations in serum T measurements deficiency and repeatedly low serum T levels, in whom re-
such that as many as 15% of healthy young men may have a mediable causes of low T have been corrected or treated
T level below the normal range in a 24-hour period (447). appropriately. This approach is consistent with that rec-
Older men with initially low T values may have normal lev- ommended by consensus panels of experts in the field
els on a subsequent blood sample. Therefore, before com- (446,454). T treatment should be instituted in these men if
mitting someone to T replacement therapy, a repeat serum T both the clinician and the patient feel that the potential ben-
level should always be obtained to confirm androgen defi- efits (e.g., severe muscle weakness, osteoporosis, or alter-
ciency. ations in sexual function or mood) of treatment outweigh
If the initial serum-free or bioavailable T level is within the potential risks (e.g., erythrocytosis and prostate disease)
the normal range in a man with symptoms and/or signs of and if no contraindications exist. Absolute contraindications
androgen deficiency, the patient’s clinical status and serum to T therapy are prostate and breast cancer, and relative con-
T levels should be monitored on follow-up visits. Finally, traindications are untreated BPH with severe bladder outlet
because clinical manifestations of androgen deficiency usu- obstruction, untreated obstructive sleep apnea syndrome,
ally have multiple etiologies in older men, evaluation and and erythrocytosis.
appropriate treatment of other causes of clinical findings
should be undertaken concomitantly with the work-up for T THERAPY AND MONITORING IN OLDER MEN
androgen deficiency.
Baseline Evaluation and Goals of T Replacement
Further Evaluation of Older Men With Low T Levels Prior to institution of T therapy, a careful baseline clinical
If the repeated serum-free or bioavailable T level is low evaluation should be performed in order to determine
and is associated with inappropriately normal or low go- whether there is a history of: prostate or breast cancer, or
nadotropin levels (i.e., a hormonal pattern of secondary hy- family history or risks for these androgen-dependent malig-
pogonadism) serum prolactin and iron should be obtained to nancies; severe symptoms of BPH [e.g., using the Interna-
rule out hyperprolactinemia and hemochromatosis (iron tional Prostate Symptom Score (IPSS) or American Urolog-
overload), both of which can suppress gonadotropin and T ical Association (AUA) Symptom Score] or sleep apnea
secretion. In individuals with very low T (e.g., total T (e.g., using the Berlin Questionnaire or Epworth Sleepiness
150 ng/dl) and low gonadotropin levels, and/or those with Scale); an abnormal digital rectal examination (e.g., indura-
markedly elevated prolactin levels (e.g., 100 ng/ml), an tion or nodule) requiring prostate ultrasound and biopsy;
MRI or CT scan of the hypothalamus and pituitary should erythrocytosis (hematocrit 52); or an elevated PSA level
be performed to rule out a tumor or destructive lesion in this 4 ng/ml (after empiric treatment for prostatitis and repeat
area (448). Men with hyperprolactinemia, hemochromato- PSA determination).
sis, or hypothalamic-pituitary tumor or destructive lesion In the absence of knowledge regarding the dose-response
should be treated appropriately with consultation from an effects of T treatment and lack of evidence for altered an-
endocrinologist. In the absence of these conditions, and in drogen requirements in older men, a reasonable goal of T
older men in whom repeated serum T level is low and is as- replacement is to restore serum T levels into the mid-normal
range for younger men and to alleviate the clinical manifes- as a result of the large surface area of skin covered. Transfer
tations of androgen deficiency. of T to partners or children is possible if the skin surface on
which T gel is applied is not covered or washed (which is
Preparations Available and Under Development for T acceptable 1 hour after application).
Replacement Therapy Oral 17 alpha-alkylated androgens (e.g., methyltestoster-
There are several formulations available for T replace- one) should not be used for androgen replacement therapy
ment therapy in older men (455,456). The most commonly (456). They are less effective than parenteral and transder-
used preparations for T replacement are parenteral 17 beta- mal T formulations and are associated with potentially seri-
hydroxy-esters of T, T enanthate, or cypionate, usually ous hepatotoxicity and greater suppression of HDL choles-
administered by intramuscular injections at a dosage of terol levels. Outside the United States, an oral T ester
150–200 mg every 2 weeks (457). These T esters are safe, formulation, T undecanoate, has been used successfully and

effective, and the least expensive formulation available for safely for many years for T replacement therapy in both
androgen replacement therapy. However, serum T levels young and older androgen-deficient men (449,456,468).
rise to supraphysiological levels during the first few days Unlike 17 alpha-alkylated androgens, T undecanoate is ab-
following injection of T esters and fall into the low-normal sorbed directly from the gastrointestinal tract into lymphat-
range or below normal just before the next injection. The ics, bypassing initial hepatic inactivation, and it is not asso-
extreme variations in T levels between injections are often ciated with hepatotoxicity (468). However, absorption of
accompanied by fluctuations in energy, libido, and mood oral T undecanoate is quite variable and is dependent on co-
that may be bothersome to patients. Transient supraphysio- ingestion of a meal. T undecanoate may become available in
logical T levels and overall higher average T levels during the United States in the future. A buccal T formulation is
treatment with T esters may be associated with a higher in- also being developed for androgen replacement therapy.
cidence of side effects, such as erythrocytosis. It is possible Both the T undecanoate and buccal T have the advantage of
that low-dosage androgen supplementation with T enan- rapid withdrawal if adverse effects develop, but the disad-
thate or cypionate (e.g., 50–100 mg every 2 weeks) may vantage of requiring twice daily administration, making
have beneficial effects (e.g., on libido, energy, and well- compliance more difficult in older patients.
being) without these side effects (458), but this has not been A number of longer-acting T formulations that require in-
evaluated in controlled clinical trials. jections only every few months are being developed for T
Three transdermal T patches are available for T replace- replacement therapy (e.g., T undecanoate, T buciclate, and
ment therapy (459,460). They require daily application but T microspheres), and T implants have been used for andro-
provide more physiological serum T levels (usually in the gen replacement outside the United States (456). Although
low- to mid-normal range) than T ester injections. T patches more convenient than currently available T esters, these
have the advantage that treatment may be discontinued rap- preparations are probably less suitable for T therapy in older
idly if adverse effects were to develop in older men, but men because rapid withdrawal of androgen would not be
they are more expensive than replacement with T ester in- possible if adverse effects were to develop during treatment.
jections. The Testoderm® patch (Alza, Palo Alto, CA) is Analogous to recently developed selective estrogen re-
effective but requires application to a clean, dry, often ceptor modulators used for hormone replacement therapy in
shaven scrotum, and many men find this site of application post-menopausal women, selective androgen receptor mod-
unacceptable (218). This patch also produces high serum ulators (SARMs) or “designer” androgens are being devel-
DHT levels, probably as a result of high 5 alpha-reductase oped for T replacement therapy. An ideal SARM would be
activity in scrotal skin. The clinical consequences of high an agent that had all the beneficial effects of T on muscle,
DHT levels, however, are not known. The Androderm® bone, sexual function, mood, cognition, and the cardiovas-
patch (Watson, Corona, CA) may be applied to nonscrotal cular system without any of the adverse effects on the pros-
skin, but the adhesive and/or enhancing agents used in this tate and cardiovascular system. 7 alpha-methyl-19-nortes-
patch may cause significant skin irritation (461–463). Skin tosterone (MENT) is synthetic androgen that does not
irritation may be reduced by coapplication of a glucocorti- undergo 5 alpha-reduction but is aromatizable to an estro-
coid cream such as triamcinolone (464). The Testoderm gen. In animal studies, it is approximately 10 times more
TTS® patch (Alza, Palo Alto, CA) is also applied to non- potent than T in suppressing gonadotropin levels and in-
scrotal skin and causes much less skin irritation because it creasing muscle size, but only two-times more active than T
has less adhesive and does not use enhancing agents (465). in stimulating prostate growth (469,470). Therefore, it is
However, it is larger than the Androderm patch and may ad- possible that a low dose of MENT given to hypogonadal
here poorly to skin, especially with vigorous exercise or ex- men may be able to maintain muscle strength and brain
cessive sweating, resulting in lower serum T levels. function without stimulating the prostate gland. MENT is
Recently, a transdermal T gel, AndroGel® (Unimed/ being developed as an implant, and preliminary studies sug-
Solvay, Buffalo Grove, IL), became available for T replace- gest that it is able to maintain libido and sexual function in
ment therapy (260,261,466,467). Daily application of this hypogonadal men (471).
hydroalcoholic gel formulation of T produces physiological
serum T levels. The dosage of T gel may be adjusted to Monitoring During T Therapy in Older Men
achieve T levels in the low-, mid-, or upper-normal range In older men, clinical examination including a digital rec-
without significant skin irritation. AndroGel may also pro- tal examination, hematocrit, and PSA should be repeated 3
duce serum DHT levels above the normal range, probably and/or 6 months after institution of T treatment, then moni-
M88 MATSUMOTO
tored every 12 months or possibly more frequently thereaf- numbers of healthy older men suggest beneficial effects
ter, depending on the clinical status of the patient. Efficacy on body composition, BMD, LDL cholesterol, angina, and
is determined primarily by subjective and objective clinical exercise-induced cardiac ischemia, and possibly muscle
responses to T therapy. If symptomatic clinical improve- strength, libido, general well-being, and certain aspects of
ment does not occur in 6–12 months and/or BMD does not cognitive function. In these studies, there have been no sig-
improve in 24 months, patients should be re-evaluated and nificant adverse effects except for erythrocytosis requiring a
discontinuation of T therapy should be considered. Serum T reduction in dose in some men. Given these findings, it is
levels measured at the midpoint of the interval between T reasonable to consider T replacement therapy in older men
ester injections or T patch applications may be useful to with a clinical syndrome consistent with androgen defi-
confirm that levels are within the midnormal range. Nadir ciency and repeatedly low serum-free and bioavailable T
serum T levels (i.e., just before the next T ester injection or levels, in whom the potential benefits of therapy outweigh

patch application) may be helpful in identifying the need for the potential risks. Because age-related alterations in physi-
a dosage adjustment. ological function are usually a result of multiple etiologies,
During T treatment, the following clinical situations re- it is important to evaluate and treat other factors (e.g., inad-
quire further urological evaluation: development of findings equate nutritional intake, confounding illness and medica-
suspicious for prostate cancer on digital rectal examination tion, inactivity or poor conditioning, excessive alcohol, and
(e.g., a nodule or induration); PSA level 4 ng/ml that is smoking) in addition to low T levels that may contribute to
not complicated by a urinary tract infection (e.g., prostatitis) the clinical syndrome.
(472,473); a confirmed increase in PSA of 1.5 ng/ml be- A major caveat in treating older men with T is that long-
tween two consecutive values over 3–6 months (474); a rate term benefits on fracture incidence, onset of dementia, ma-
of rise in PSA levels of 0.75 ng/ml/y on sequential val- jor cardiovascular outcomes, physical function, frailty and
ues performed over at least 2 years (475); or severe symp- quality of life, and risks of clinical prostate disease (BPH
toms of BPH (e.g., as assessed using the AUA Symptom and prostate cancer) and cardiovascular disease are not
Score or IPSS instruments) that are not complicated by known. Therefore, routine T treatment of older men cannot
medications (e.g., decongestants or antihistamines) or a uri- be recommended. The balance of benefits and risks of T
nary tract infection (e.g., prostatitis). A urological evalua- therapy in older men with low T levels needs to be deter-
tion including a transrectal ultrasound and prostate biopsy is mined in carefully designed, large, long-term, randomized,
indicated for an abnormal digital rectal examination or PSA placebo-controlled studies. Until the results of these studies
elevation (i.e., a persistent elevation of PSA after empiric are available, practitioners must rely on sound clinical judg-
antibiotic treatment for prostatitis). Development of an in- ment in managing older men with symptoms and signs of
crease in hematocrit 52% requires reduction in T dosage andropause. At present, the most prudent course of action is
or discontinuation of therapy. For severe erythrocytosis to treat only older men with repeatedly low serum T levels
(e.g., hematocrit 55%), T therapy should be discontinued, and symptoms and signs consistent with androgen defi-
and a therapeutic phlebotomy should be performed to ciency in whom the potential benefits of therapy clearly out-
acutely reduce the red cell mass and prevent hyperviscosity. weigh the potential risks, and to carefully monitor treated
After the hematocrit is normalized, T treatment may be rein- men for adverse effects. Attention to appropriate exercise
stituted using a lower dosage or a transdermal formulation. and nutrition, and evaluation and treatment of other etiolog-
Other causes of erythrocytosis (e.g., obstructive sleep apnea ical factors that may contribute to clinical manifestations
that may be induced or worsened by T treatment, or chronic are essential for optimal management of age-related func-
hypoxic lung disease) should be evaluated and treated ap- tional decline in older men.
propriately. The development of daytime somnolence, loud
snoring, hypertension, edema, and erythrocytosis in an Acknowledgments
obese older man on T therapy suggests obstructive sleep ap- This work was supported by the Department of Veterans Affairs Medi-
nea syndrome. Instruments such as the Berlin Questionnaire cal funds and NIH Grant HD12629.
or Epworth Sleepiness Scale may be used to assess symp- Address correspondence to Alvin M. Matsumoto, MD, V.A. Puget
toms of sleep apnea. Sound Health Care System, 1660 South Columbian Way (S-182-GRECC),
Seattle, WA 98108-1597. E-mail: [email protected]
SUMMARY AND CONCLUSIONS
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Prostate-sparing effects in primates of the potent androgen 7 alpha- Received July 20, 2001
methyl-19-nortestosterone: a potential alternative to testosterone for Accepted August 3, 2001

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Journal of Gerontology: MEDICAL SCIENCES In the Public Domain

Andropause: Clinical Implications of the Decline

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I T is now well accepted that serum testosterone (T) levels

Age-Related Decline in Serum T Levels

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extending throughout the life span of an individual, not just

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