How to recognize late-onset hypogonadism in men with
Giovanni Corona1,2, Giulia Rastrelli1, Linda Vignozzi1, Edoardo Mannucci3, Mario Maggi1
Late-onset hypogonadism (LOH) has been considered the most common form of male hypogonadism with a prevalence of
approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone (T)
levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific
symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important
of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T (different thresholds),
sexual parameters, medical history data (delayed puberty, pituitary disease or cryptorchidism) and their physical exam results.
Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the
together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews,
such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting
low T levels.
Asian Journal of Andrology (2012) 14, 251–259; doi:10.1038/aja.2011.138; published online 30 January 2012
Keywords: late-onset hypogonadism (LOH); male hypogonadism; testosterone; sexual dysfunction
The testis (the male gonad) continuously produces sex steroids
(mostly testosterone (T)) and sperm soon after the onset of puberty.
Testis activity is regulated by intratesticular factors (including T) and
by extratesticular trophic factors released from the pituitary (i.e.,
gonadotropin luteinizing hormone (LH)andfollicle-stimulating hor-
mone (FSH)), which are strictly regulated by the hypothalamic pep-
tide gonadotropin-releasing hormone (GnRH). Male hypogonadism
is a failure in testis activity that is classically considered to be a partial
or total communication breakdown among the hypothalamus, the
pituitary and the testis itself. Current definitions of hypogonadism
rely on T deficiency more than abnormal sperm production, but from
a conceptual point of view, both factors contribute to testicular func-
tion and dysfunction.
CLASSIFICATION OF MALE HYPOGONADISM: TOWARDS A
According to a categorical taxonomy often reported in medical text-
books, male hypogonadism is divided into primary (i.e., caused by
an abnormality of the testes) and secondary (i.e., caused by pituitary
or hypothalamic dysfunction) hypogonadism. In primary hypogo-
nadism, the testis is dysfunctional and fails to release sex steroids and
sperm, even though it is superstimulated by the pituitary gland,
whereas in secondary hypogonadism, the testis is normal but is
inadequately stimulated by gonadotropins. Hence, the first type of
hypogonadism is also defined as hypergonadotropic and the second
type as hypogonadotropic. Furthermore, a compensatory form (nor-
mal T and elevated LH) of hypogonadism has also been reported.1A
hypogonadism-like syndrome can also result from a reduced sens-
itivity, or insensitivity, to T and its metabolites (dihydrotestosterone
and oestrogens) or from reduced bioavailability of the hormone due
to an increase in its carrier protein, sex hormone-binding globulin.
Male hypogonadism can be congenital (e.g., Klinefelter’s syndrome)
or can be acquired later on, during childhood or adult life (e.g.,
following chemotherapy). This categorical classification is quite use-
ful for selecting the most appropriate therapy for individual patients
but is largely unsatisfactory in describing the clinical picture and
patient phenotype. With respect to therapy, patients with hypotha-
lamic or pituitary causes of testis failure (hypogonadotropic or se-
condary hypogonadism) can be successfully treated by removing the
precipitating cause (for example, prolactinoma) and/or by appro-
priate endocrine therapy (i.e., gonadotropins or GnRH for desired
fertility, or T for virilisation, if fertility is not the primary goal).
However, hypogonadism is more a dimensional disorder rather than
a categorical one; in clinical practice, both primary (testis) and se-
condary (hypothalamus and/or pituitary) failure are often simulta-
neously present, as in the case of hypogonadism associated with
obesity or metabolic syndrome. In addition, signs and symptoms
of hypogonadism are quite similar, irrespective of the disease origin;
in other words, the clinical phenotype can be identical for primary or
1Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence 50139, Italy;2Endocrinology Unit, Maggiore-Bellaria Hospital,
Medical Department, Azienda-Usl Bologna, Bologna 40133, Italy and3Diabetes Section Geriatric Unit, Department of Critical Care, University of Florence, Florence 50139, Italy
Correspondence: Professor M Maggi (email@example.com)
Received: 30 June 2011; Revised: 31 July 2011; Accepted: 11 August 2011; Published online: 30 January 2012
Asian Journal of Andrology (2012) 14, 251–259
? 2012 AJA, SIMM & SJTU. All rights reserved 1008-682X/12 $32.00
secondary hypogonadism.2–4However, the clinical phenotype is very
different according to the age of hypogonadism onset, which can be
used as an alternative classification. Table 1 reports the new age-of-
onset-based classification of male hypogonadism. When the problem
occurs during early foetal life (very-early-onset hypogonadism),
symptoms can be dramatic, from an almost complete female pheno-
type (complete androgen insensitivity or enzymatic defects blocking
androgen synthesis) to various defects in virilisation (micropenis,
hypospadias cryptorchidism), as in the case of impaired secretion
or activity of GnRH. Differences in the severity of the phenotype
arise from the presence or absence of a temporary GnRH-indepen-
dent/human chorionic gonadotropin-dependent T secretion from
the foetal testis. In the case of the peripubertal appearance of hypo-
gonadism (early-onset hypogonadism), because of milder central or
peripheral defects (such as in Klinefelter’s syndrome), there might be
a delay in the onset of puberty with an overall eunuchoidal pheno-
type, including scant body hair, a high-pitched voice and a small
testis, penis and prostate. However, when hypogonadism develops
after puberty, and specifically, when it occurs with ageing (late-onset
hypogonadism (LOH)), the symptoms will be relatively mild, insi-
dious and difficult to recognize. These symptoms include the follow-
ing: loss of muscle mass and strength, physical activity and
performance decline, decrease in some cognitive abilities, depressive
symptoms and sexual dysfunction.4,5However, these symptoms
are not specific enough to be considered pathognomonic, which
makes differential diagnosis between LOH and physiological ageing
Despite the unimpressive clinical picture, LOH should not be over-
looked. It is important to note that LOH symptoms can place a sig-
nificant burden on both the patient and the healthcare system. LOH
can impact the patient’s physical, social, emotional, cognitive and
sexual functioning,5,6which are all key domains inherent to health-
related quality of life.7,8Furthermore, male hypogonadism has also
ber of symptoms, including fatigue, low mood (which can lead
to depression12,13) and loss of bone density (which may lead to
osteoporosis14,16) have the potential to cause considerable short-term
and long-term disabilities with economic consequences.17LOH is the
most common form of male hypogonadism, with even the most con-
servative estimate recognizing a prevalence of 1–2:100 adult males
(Table 1).4,18However, few data on hypogonadism in ageing men are
men lacking pathological hypogonadism have not been determined.1
Figure 1 summarizes the most common clinical illnesses associated
with an increased risk of LOH for which the evaluation of T is
Among the different symptoms, sexual dysfunction is the most
important determinant for medical consultation4and the most spe-
cific symptom associated with low T.18In fact, recent data from the
European Male Aging study recognized that a triad of sexual symp-
toms (low libido as well as reduced spontaneous and sex-related erec-
tions) is the only syndromic association with decreased T levels,18
whereas other proposed hypogonadal symptoms did not segregate
with androgen deficiency. The lower the T levels are, the higher the
number of sexual symptoms describing hypogonadism becomes.
LOH recognition has been greatly helped by the recent consensus
among professional societies (see also Table 2).5,19,20Although they
differ in their proposed T thresholds for the biochemical definition of
hypogonadism,2–4all the Andrology Society guidelines recognize that
the presence of hypogonadism-related symptoms is the cornerstone to
defining a clinically relevant hypogonadism. It has been universally
recognized that diagnosis of androgen deficiency should be made only
in symptomatic men with unequivocally low serum T levels, as neither
marker is consistently reliable alone. For all the guidelines, the total T
should be sampled in the morning on at least two separate occasions
before making a diagnosis. T substitution should be offered to symp-
tomatic individuals when circulating total T is below 8 nmol l21
(231 ng dl21).5In addition, there is also a general agreement that
total T level above 12 nmol l21(346 ng dl21) does not require
supplementation. When the total T is between 8 and 12 nmol l21in
the presence of typical hypogonadal symptoms, a T treatment trial
should be considered.5Measurement of free T (FT) by equilibrium
dialysis or calculation (cFT) according to Vermuelen’s formula
(http://www.issam.ch/freetesto.htm) might help in conditions when
sex hormone-binding globulin could be decreased (obesity, acro-
megaly, hypothyroidism) or increased (ageing, hepatic illnesses,
hyperthyroidism, use of anticonvulsants). Conversely, the immuno-
metric method for evaluation of FT has been considered unreliable.2–4
HOW TO RECOGNIZE LOH IN MEN WITH SEXUAL
To determine the symptoms and signs that are specifically associated
with low T, we retrospectively analysed data of 1734 men that con-
sulted an andrology clinic for sexual dysfunction. All of them were
symptomatic by definition because they complained of sexual pro-
blems. The results are reported in Figures 2–4, stratified according
to the median age of the cohort studied (53 years). Only metrics
associated with severe (total T below 8 nmol l21) or mild (total T
below 12 nmol l21) hypogonadism are depicted and reported as
hazard ratio (age-adjusted) in a log scale. By using these criteria, 472
(27.7%) patients exhibited mild hypogonadism, while 128 (7.4%) of
the patients had severe hypogonadism. In particular, severe hypogo-
nadism was detected in 53 (6.2%) younger patients and 75 (8.6%)
older patients, while mild hypogonadism occurred in 198 (23.2%)
younger patients and 274 (31.1%) older patients. Figure 2 shows
the medical history-derived information that showedsignificant asso-
ciation with a severe or milder reduction of total T in our series. As
expected, a history of delayed puberty, pituitary disease and cryp-
torchidism were all associated with severe hypogonadism in both
younger and older subjects. The milder form of hypogonadism was
only significantly associated with delayed puberty in both cohorts,
while cryptorchidism was significant only in the oldest groups, and
population, self-reported extramarital activity is a negative predictor
of mild, but not severe, hypogonadism. In the oldest cohort, any form
as decreased libido, frequency of sexual intercourse, morning and
sexual-related erections, and perceived reduced ejaculate volume.
Only decreased sexual desire and morning erections predicted any
form of hypogonadism in the youngest cohort. A reduced frequency
of autoerotism (masturbation) characterized any T deficiency in the
youngest, but not in the oldest, cohort. In both populations, a milder
most likely because hypogonadism reduces male sexual confidence
and related aggressiveness. People with a milder reduction in T felt
guiltier with autoeroticism than their eugonadal counterpart.
and laboratory findings. Irrespective of age, the presence of a reduced
testis volume strongly suggests a reduction of total T. Similar results
G Corona et al
Asian Journal of Andrology
cases of severe hypogonadism. Other clinical signs, such as increased
waist circumference, might help identify hypogonadism, but only the
clustering of several symptoms and signs, such as those reported in
ANDROTEST, results in a reliable screen for this condition. Using
ANDROTEST in subjects with sexual dysfunction might identify a
severe form of male hypogonadism with acceptable sensitivity and spe-
cificity (almost 70%).
1Tajar A, Forti G, O’Neill TW, Lee DM, Silman AJ et al. Characteristics of secondary,
primary, and compensated hypogonadism in aging men: evidence from the European
Male Ageing Study. J Clin Endocrinol Metab 2010; 95: 1810–8.
Buvat J, Maggi M, Gooren L, Guay AT, Kaufman J et al. Endocrine aspects of male
sexual dysfunctions. In: Montorsi F, Basson R, Adaikan G, Becher E, Clayton A,
Giuliano G, Khoury S, Sharlip I, editors. Sexual Medicine, Sexual Dysfunctions in
Men and Women. Proceedings of the 3rd International Consultation on Sexual
Medicine. Paris: Health Publication Ltd; 2010. p681.
Morelli A, Corona G, Filippi S, Ambrosini S, Forti G et al. Which patients with sexual
dysfunction are suitable for testosterone replacement therapy? J Endocrinol Invest
2007; 30: 880–8.
Corona G, RastrelliG, Forti G, MaggiM. Update in testosterone therapyfor men.J Sex
Med 2011; 8: 639–54.
Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ et al. Investigation,
treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU,
EAA and ASA recommendations. Eur J Endocrinol 2008; 159: 507–14.
Novak A, Brod M, Elbers J. Andropauseand qualityof life: findings from patientfocus
groups and clinical experts. Maturitas 2002; 43: 231–7.
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality
of life. Health Policy 1990; 16: 199–208.
Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I.
Conceptual framework and item selection. Med Care 1992; 30: 473–83.
Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and
mortality in male veterans. Arch Intern Med 2006; 166: 1660–5.
associated with an increased risk of MACE lethality in subjects with erectile
dysfunction. J Sex Med 2010 (4 Pt 1); 1557–64.
Corona G, Rastrelli G, Vignozzi L, MannucciE, Maggi M. Testosterone,cardiovascular
Burris AS, Banks SM, Carter CS, Davidson JM, Sherins RJ. A long-term, prospective
study of the physiologic and behavioral effects of hormone replacement in untreated
hypogonadal men. J Androl 1992; 13: 297–304.
Corona G, Ricca V, Bandini E, Mannucci E, Petrone L et al. Association between
psychiatric symptoms and erectile dysfunction. J Sex Med 2008; 5: 458–68.
FinkelsteinJS, KlibanskiA,NeerRM, GreenspanSL, RosenthalDIetal.Osteoporosis
in menwithidiopathic hypogonadotropic hypogonadism.AnnInternMed1987; 106:
Greenspan SL, Neer RM, Ridgway EC, Klibanski A. Osteoporosis in men with
hyperprolactinemic hypogonadism. Ann Intern Med 1986; 104: 777–82.
loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J Clin
Endocrinol Metab 1989; 69: 523–7.
17Maggi M, Schulman C, Quinton R, Langham S, Uhl-Hochgraeber K. The burden of
testosterone deficiency syndrome in adult men: economic and quality-of-life impact.
J Sex Med 2007; 4: 1056–69.
Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ et al. Identification of late-onset
hypogonadism in middle-aged and elderly men. N Engl J Med 2010; 363: 123–35.
Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ; American
Association of Clinical Endocrinologists. American Association of Clinical
Endocrinologists Medical Guidelines for clinical practice for the evaluation and
treatment of hypogonadism in adult male patients-2002 update. Endocr Pract
2002; 8: 440–56.
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ et al. Testosterone
therapy in men with androgen deficiency syndromes: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 2010; 95: 2536–59.
Crown S, Crisp AH. A short clinical diagnostic self-rating scale for psychoneurotic
patients. The Middlesex Hospital Questionnaire (M.H.Q.). Br J Psychiatry 1966;
Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P et al. Validation of a screening
questionnaire for androgen deficiency in aging males. Metabolism 2000; 49: 1239–
Heinemann LA, Saad F, Heinemann K, Thai DM. Can results of the Aging Males’
Symptoms (AMS) scale predict those of screening scales for androgen deficiency?
Aging Male 2004; 7: 211–8.
Smith KW, Feldman HA, McKinlay JB. Construction and field validation of a self-
administered screener for testosterone deficiency (hypogonadism) in ageing men
Clin Endocrinol (Oxf) 2000; 53: 703–11.
Rosen RC, Araujo AB, Connor MK, Gerstenberger EP, Morgentaler A et al. The NERI
Hypogonadism Screener: psychometric validation in male patients and controls. Clin
Endocrinol 2011; 74: 248–56.
deficiency in aging males (ADAM) questionnaire for the identification of
hypogonadism in elderly community-dwelling male volunteers. Eur J Endocrinol
2004; 151: 355–60.
Morley JE, Perry HM 3rd, Kevorkian RT, Patrick P. Comparison of screening
questionnaires for the diagnosis of hypogonadism. Maturitas 2006; 53: 424–9.
Chu LW, Tam S, Kung AW, Lam TP, Lee A et al. A short version of the ADAM
Questionnaire for androgen deficiency in Chinese men. Gerontol A Biol Sci Med Sci
2008; 63: 426–31.
Blu ¨mel JE, Chedraui P, Gili SA, Navarro A, Valenzuela K et al. Is the Androgen
Deficiency of Aging Men (ADAM) questionnaire useful for the screening of partial
androgenic deficiency of aging men? Maturitas 2009; 63: 365–8.
Martı ´nez-Jabaloyas JM, Queipo-Zaragoza ´ A, Rodrı ´guez-Navarro R, Queipo-Zaragoza ´
JA, Gil-Salom M et al. Relationship between the Saint Louis University ADAM
questionnaire and sexual hormonal levels in a male outpatient population over 50
years of age. Eur Urol 2007; 52: 1760–7.
Emmelot-Vonk MH, Verhaar HJ, Nakhai-Pour HR, Grobbee DE, van der Schouw YT.
Low testosterone concentrations and the symptoms of testosterone deficiency
according to the Androgen Deficiency in Ageing Males (ADAM) and Ageing Males’
Symptoms rating scale (AMS) questionnaires. Clin Endocrinol (Oxf) 2011; 74:
Corona G, Jannini EA, Maggi M. Inventories for male and female sexual dysfunctions.
Int J Impot Res 2006; 18: 236–50.
Fairburn CG, Peveler RC, Davies B, Mann JI, Mayou RA. Eating disorders in young
adults with insulin dependent diabetes mellitus: a controlled study. BMJ 1991; 303:
Corona G, Mannucci E, Petrone L, Balercia G, Fisher AD et al. ANDROTEST: a
structured interview for the screening of hypogonadism in patients with sexual
dysfunction. J Sex Med 2006; 3: 706–15.
G Corona et al
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