Overview of Hypogonadism defined

Male hypogonadism is a clinical syndrome resulting from a failure of the testes to produce physiological levels of testosterone (androgen deficiency), sperm, or both, because of disruption of one or more levels of the hypothalamic-pituitary-gonadal axis.1 Hypogonadism can occur in men of any age, however, there is a progressive decline in testosterone levels as men age. Late-onset hypogonadism (LOH; age-related hypogonadism) is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels below the young healthy adult male reference range of approximately 10–35 nmol/L (300–1000 ng/dL).2,3

Unlike the clearly defined decrease in hormone levels associated with female menopause, the decline in androgen levels with advancing age in men is gradual and variable, and the late-onset hypogonadism is more appropriate than the colloquial terms “male menopause” or “andropause” to refer to the annual decrease in testosterone levels of 0.5% to 2% which occur with advancing age, independent of chronic conditions associated with aging.4

Although hypogonadism is a relatively common disorder, the exact prevalence is uncertain. However, it is clear that hypogonadism affects a significant proportion of the aging male population and its incidence can be expected to increase as a result of the aging population, increased life expectancy, and the increasing prevalence of type 2 diabetes mellitus, metabolic syndrome, obesity, and other risk factors for hypogonadism.

Using the standardized and widely-used AMS scale, the prevalence of moderate-to-severe hypogonadism was estimated at approximately 20% in European men aged over 50 years.5 Thus, in the European Union, approximately 81 million men aged 50 years and over are at risk of hypogonadism.

The AMS (Aging Males’ Symptoms) scale is a 17-point self-rating questionnaire designed to help assess the symptoms of testosterone deficiency and monitor treatment-related changes if a diagnosis of hypogonadism is confirmed and testosterone replacement therapy initiated.

When hypogonadism is defined on the basis of a combination of testosterone and signs and symptoms according to the current Endocrine Society guidelines1, other population-based studies have estimated an overall prevalence in men aged 30 years and over of 5.6%, rising to 18.4% among 70-year olds.6 Approximately 40% of men aged 45 years or over (mean age 60.5 years; range 45–96 years) screened in primary care had hypogonadism (defined as testosterone <300 ng/dL), with significantly higher rates in men with hypertension, hyperlipidemia, obesity, diabetes, prostate disease, and asthma or chronic obstructive pulmonary disease.7 However, despite hypogonadism affecting a substantial proportion of the adult male population, only a small proportion are being treated for hypogonadism and, according to independent medical policy analysis, the condition is probably underdiagnosed.8

Table1: Estimates of Men in Europe at Risk of Hypogonadism
(numbers in millions; estimates made around 2006).

Region Age 50–64 Age 65–79 Age 80+
Whole European Union 42.53 29.61 9.63
France 5.32 3.45 1.36
Germany 6.48 5.21 1.58
Ireland 0.33 0.17 0.04
Italy 5.23 4.17 1.46
Spain 3.44 3.25 1.23
United Kingdom 4.99 3.26 1.23
Figures from Carruthers M. The Aging Male 2009; 12(1):21-28

How are men affected by hypogonadism?
The essential role of testosterone in the health and well-being of males is well established. Testosterone is responsible for typical male sexual characteristics and is required for a healthy life physically and psychologically, enabling and maintaining erectile function, libido, and overall sexual satisfaction. Testosterone also helps to maintain body composition and bone mass, positive mood, and physical energy. Accordingly, the health consequences of hypogonadism can be quite wide-ranging, and include fatigue, depression, erectile dysfunction, loss of libido, loss of facial and body hair, decrease in muscle mass, development of gynecomastia, and osteoporosis.

Low testosterone can be diagnosed by an assessment of symptoms and a blood test to measure testosterone levels. If tests confirm hypogonadism, a range of different testosterone replacement therapies and formulations are available to normalize testosterone levels.

How important is it to treat hypogonadism?
There are clearly established links between hypogonadism and depression, cardiovascular risk, diabetes and metabolic syndrome, osteoporosis, and other chronic illnesses.

Low testosterone values are also associated with increased mortality, even after adjusting for age, comorbidities, and other clinical covariates.

Figure: Reduced Survival in Men with Low Testosterone Levels
Testosterone replacement therapy can improve libido, mood, increase bone density, and improve body composition and quality of life in hypogonadal men. Treatment may also improve insulin resistance, reduce central obesity, and improve other risk factors for cardiovascular disease.Current treatment and controversies

Current treatment and controversies
Testosterone replacement therapy forms the core of treatment for all types of hypogonadism. A number of different androgen preparations and dosage forms are available, including injections, gels, skin patches, and capsules, and treatment can be individualized to achieve the goal of returning testosterone to physiological levels.

Correct diagnosis of hypogonadism is essential before treatment is initiated. However, the diagnosis of hypogonadism has been the subject of controversy, and there is debate about threshold levels for determining hypogonadism, the ideal manner in which to measure testosterone levels, and whether total testosterone, free testosterone, or bioavailable testosterone is the most appropriate hormone fraction to use in determining hypogonadism. In particular, the high prevalence of hypogonadism symptoms in the aging male population and the non-specific nature of these symptoms can make diagnosis difficult, and there is increasing consensus that hypogonadism should be defined by a combination of low testosterone levels and the presence of one or more signs or symptoms of hypogonadism.

The recommendations of recent international consensus documents on the diagnosis, treatment, and monitoring of hypogonadism are outlined in the Diagnosis section. Testosterone replacement therapy is generally associated with a wide margin of safety and good tolerability. However, as with any clinical intervention, the initiation of testosterone replacement therapy should be undertaken on a balance of risk versus benefit. At present, limited data are available about the long-term safety in elderly men, and discussion about if and when to treat late-onset hypogonadism continues. If a diagnosis of hypogonadism is confirmed (symptoms and total testosterone levels between 8–12 nmol/L [231–346 ng/dL]) and the patient is without contraindications, testosterone replacement therapy can be considered.1,2top of page

1 Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006; 91(6): 1995-2010

2 Wang, C., E. Nieschlag, R. Swerdloff, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol 2008, 159(5): 507-514.

3 Larsen P, Kronenburg H, Melmed S, et al. William's Textbook of endocrinology, reference values. Philadelphia, PA, USA: Saunders; 2002

4 Seftel AD. Male hypogonadism. Part I: Epidemiology of hypogonadism. Int J Impot Res 2006; 18(2): 115-20

5 Heinemann LA. Aging Males' Symptoms scale: a standardized instrument for the practice. J Endocrinol Invest 2005; 28(11 Suppl Proceedings): 34-8

6 Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 2007; 92(11): 4241-7

7 Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60(7): 762-9

8 Liverman CT, Blazer DG, Editors. Testosterone and Aging: Clinical Research Directions. Washington, DC, USA: Institute of Medicine of the National Academies; 2003 November 11, 2003