About hypogonadism

    What is hypogonadism?

    Male hypogonadism is a clinical condition 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. Lateonset hypogonadism (LOH; age-related hypogonadism) is a clinical and biochemical syndrome associated with advancing age and characterised by symptoms and a deficiency in serum testosterone levels below the young healthy adult male reference range of approximately 12–35 nmol/L (300–1000 ng/dL).2,3,4

     

    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 term ‘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 ageing.5

    Hypogonadism and testosterone therapy

    Fundamental concepts regarding hypogonadism and testosterone therapy:

    International Expert Consensus Resolutions

    In 2015, an international expert consensus conference about hypogonadism (testosterone deficiency) and its treatment was held in Prague, sponsored by King’s College London and the International Society for the Study of the Ageing Male (ISSAM).2 The impetus for this meeting was to address the widespread misinformation and confusion about hypogonadism and testosterone therapy.12 The ultimate goal of this consensus conference was to document what is true or untrue about hypogonadism and testosterone therapy, to the best degree possible based on existing scientific and clinical evidence, as summarised in table 1.2

    Table 1: Resolutions of the International Expert Consensus Conference on testosterone deficiency (hypogonadism) and testosterone therapy.2

    Resolutions Expert comments

    1. TD is a well-established, significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life.

    TD (low levels of testosterone):

    • May predict increased risk of developing diabetes, metabolic syndrome.
    • Contributes to decreased bone mineral density.
    • Is associated with increased all-cause and cardiovascular mortality.
    • Negatively impacts general health and quality of life.

    2. The symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying cause.

    • Symptoms and signs of TD occur in patients who undergo androgen deprivation; these symptoms and signs may resolve with T normalisation.
    • Historically recognised causes of TD are rare (e.g., anorchia, craniopharyngioma, pituitary tumor), recently termed classical hypogonadism. These conditions account for only a tiny fraction of men with TD.
    • TD occurs frequently with conditions other than “classical” causes.
    • No evidence exists to support restriction of T therapy only to men with known underlying cause.

    3. TD is a global public health concern.

    • Prevalence rates in men range from 2% to 38% in studies from Asia, Europe, North America, and South America.
    • Variation in prevalence rates can be explained by differences in the definition of TD and T thresholds.
    • A US study estimates an additional $190-$525 billion in health care expenditures over 20 years due to TD.

    4. T therapy for men with TD is effective, rational, and evidence based.

    High-level evidence shows T therapy may effectively:

    • Increases sexual desire (libido) and erectile and orgasmic function.
    • Increases lean body mass.
    • Decreases fat mass.
    • Improves bone mineral density.

    Strongly suggestive evidence for improvement in mood and energy

    5. There is no T level threshold that reliably distinguishes those who will respond to treatment from those who will not.

    No study has revealed a single testosterone threshold that reliably separates those who experience signs and symptoms of TD from those who do not, nor who will likely respond to treatment.

     

    Interpretation of total T levels is confounded by:

    • Interindividual variation.
    • Variation in serum SHBG (binds tightly to T, removing it from the bioavailable pool).
    • Genetic variation in androgen receptor sensitivity.

    Free T can be a useful indicator of androgen status.

    6. There is no scientific basis for any age-specific recommendations against the use of T therapy in men.

    • The term age-related hypogonadism is of questionable validity since the decline in mean serum T level with age is minor and primarily attributable to comorbidities, especially obesity.
    • Older men respond well to T therapy, as do younger men.
    • Increased risk of erythrocytosis (increased red blood cell mass) in older men requires monitoring but does not merit withholding T therapy if indicated.
    • It is illogical to single out TD as the one medical condition among many (e.g., diabetes, hypertension, heart disease, cancer, arthritis) that does not merit treatment because it becomes more prevalent with age.

    7. The evidence does not support increased risks of CV events with T therapy.

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    • Two observational studies received intense media attention after reporting increased CV risks. Both had major flaws/limitations. One misreported result, the other had no control group.
    • Low serum T is associated with increased atherosclerosis, coronary artery disease, obesity, diabetes, and mortality.
    • Several RCTs in men with known heart disease (angina, heart failure) showed greater benefits with T vs placebo (greater time to ischemia, greater exercise capacity).
    • No increased risk of blood clots (VTE) with T therapy.

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    8. The evidence does not support increased risk of PCa with T therapy.

    • Blood androgen levels are not associated with increased risk of PCa nor aggressive PCa.
    • T therapy has no greater risk of PCa than placebo.
    • Aggressive/high-grade PCa is associated with low serum T levels.
    • Early data suggest no increased risk of recurrence/progression with T therapy in men previously treated for PCa.

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    9. Evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes.

    • A large body of evidence suggests lower serum T concentrations are associated with increased CV risk; higher levels are protective.
    • T therapy may increase lean mass, decreases fat mass, and may improve glycemic control.10
    • Mortality rates are reduced by half in men with TD who received T therapy compared with untreated men in observational studies.
    • Among men who received T therapy, those with normalised T levels had a reduced rate of CV events/mortality vs men with persistently low T.

    Abbreviations: CV; cardiovascular; PCa; prostate cancer; RCT; randomised controlled trial; SHBG; sex hormone binding globulin; T; testosterone; TD; testosterone deficiency; VTE; venothrombotic events.

    How common is hypogonadism?

    The prevalence of hypogonadism varies and is particularly high in the large population of men with obesity, type 2 diabetes and erectile dysfunction.11

    Among men aged ≥45 years visiting primary care offices, the prevalence of hypogonadism (defined as TT levels <300 ng/dl or current androgen treatment) has been shown to be nearly 40% (2162 patients).13 In men with obesity (BMI ≥30 kg/m²), hypogonadism was present in up to 58% (96 patients), despite the relatively young mean age of 43 years,14 while in a population of men with severe obesity (age 40 years) referred for bariatric surgery, nearly 80% (26 patients) had hypogonadism.15

    Men with type 2 diabetes tend to have a higher prevalence of low free testosterone than low total testosterone.16-18 For instance, in one study 20% of men with type 2 diabetes had low total testosterone, and 50% had low free testosterone (calculated).16 In another study of men with type 2 diabetes, 49% (241 patients) had low total testosterone (defined as <12.1 nmol/L) while 58% (267 patients) had low free testosterone.17 Based on either total or free testosterone being low, prevalence was ~69%.17 Yet another study found that 45% (52 patients) and 61% (70 patients) of men with type 2 diabetes had low total and calculated free testosterone levels, respectively.18 Notably, even younger men (between the ages of 18 and 35 years) with type 2 diabetes have a similarly high prevalence of hypogonadism at 58% (14 patients) when the normal range from a study on younger male subjects aged 20-29 was used.6,*

    Among men with erectile dysfunction, up to half (47% - 1313 patients) have hypogonadism; an abrupt increase in hypogonadism prevalence has been seen in men aged 45 to 50, beyond which a plateau of prevalence was maintained until older than 80 years of age.19

    The prevalence of obesity in the U.S. in men aged 20 years and older is now 38%, and has reached 41% in the 40-59 year age group.21 In 2014, the global age-standardised prevalence of diabetes in men had increased from 4.3% in 1980 to 9.0%.22 Rising levels of adiposity explain the large majority of the rise in diabetes prevalence,21 and obesity is considered the main preventable and treatable cause of type 2 diabetes.23,24 In the Massachusetts Male Ageing Study (MMAS), the prevalence of erectile dysfunction was 52% in 40- to 70-year-old men in the general population.25 Obesity is also a strong risk factor for erectile dysfunction.26

    Considering the exceptionally high prevalence of obesity, type 2 diabetes and erectile dysfunction, and the common occurrence of hypogonadism in these men, measuring testosterone levels in these men is warranted. The 2016 American Association of Clinical Endocrinologists (AACE) / American College of Endocrinology (ACE) clinical practice guidelines for medical care of patients with obesity recommends that all men who have an increased waist circumference (>94-102 cm or >37-40 inches) or who have obesity should be assessed for hypogonadism by history (inquiring about symptoms) and physical examination, have testosterone levels measured and be offered testosterone therapy if indicated.26 Likewise, all men with type 2 diabetes should be evaluated to exclude testosterone deficiency.27 In 2018, the American Diabetes Association (ADA) added to their Standards of Medical Care in Diabetes the recommendation to consider checking serum testosterone in men with diabetes and signs and symptoms of hypogonadism,28 and expert clinicians have also made a strong case for measuring total testosterone and calculating free testosterone in routine diabetic care.17

    * The prevalence of hypogonadism was 33% based on standard normal ranges. However, when the normal range from a study on younger male subjects was used (20-29 years), 58% were subnormal.

    How are men affected by hypogonadism?

    Testosterone is not just a sexual hormone, it is also a metabolic hormone and a vascular hormone that may play an important role in metabolic and vascular health.33,34 The metabolic effects of testosterone explain why low testosterone is associated with the development of obesity, metabolic syndrome and type 2 diabetes.34-39 Testosterone is also a vasoactive hormone with predominantly vasodilatory actions.33 In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and blood flow, improves cardiac ischemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure.32,40 Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells.33 Studies have shown testosterone may be beneficially associated with key mediators of atherosclerosis,41 including lipids,42,43 endothelial dysfunction44 and inflammation.45 Study findings raise the possibility that individuals with TD might benefit from TRT to decelerate progression of atherosclerosis, as measured by carotid intima-media thickness. However, some studies have found no association between testosterone and cIMT.46-48 Hence, low testosterone is a marker of cardiovascular risk, and may even be a cardiovascular risk factor itself.*49-50

    Emerging research suggests that testosterone, or its metabolite DHT, may be positively associated with telomere length, which is a cellular marker for biological ageing.51,52 Experimental studies support the hypothesis that testosterone delays vascular smooth cell senescence, and vascular and cardiomyocyte ageing.53,54

    In addition to physical and metabolic effects, testosterone appears to play a key role in mood and mental health; however, with regard to cognitive function, it is very difficult to conclude how testosterone affects cognitions and emotions.55,56 Men over the age of 45 with low testosterone levels have a 4-fold increased risk of developing depression over the next two years.57 In a separate study among older men with low testosterone, the prevalence of anxiety disorders, depressed mood and major depressive disorder is significantly (P<0.05) higher than in men with healthy levels of testosterone.58,59 However, one study found androgens were not independently associated with depressive symptoms among men and women from the general population. Further investigations in large-scale studies are needed to elucidate the impact of androgens on depression and relevant cofounders. Vice versa, men aged 65 years and older with depression have been observed to have significantly lower free testosterone concentrations than nondepressed men.60 It has been suggested that low testosterone may be a potentially treatable cause of depressive symptoms.60 While hormonal flux in females appears to increase the likelihood of experiencing mood disturbances, clinical and preclinical studies in males suggest that testosterone yields protective benefits against anxiety and depression.

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    Why is it important to treat hypogonadism?

    There is now convincing evidence that low testosterone is closely associated with cardiovascular risk factors as well as the presence and degree of atherosclerosis, and is a marker for premature death.50

    It is very important to treat men with hypogonadism because hypogonadism is associated with increased all-cause mortality,63-66 independent of waist circumference, smoking habits, high-risk alcohol use, physical activity and renal insufficiency.67 Notably, the association between low testosterone and all-cause mortality persists even after adjustment for age and comorbidities. 64,67,68 It is noteworthy that even young men with low testosterone are at increased risk of death.67

    Critically, a growing body of evidence shows that testosterone therapy in men with hypogonadism has been associated with decreased mortality compared to men with hypogonadism who do not receive testosterone therapy; however, further investigation is warranted to better understand the effect of testosterone treatment on the health of older men.69-78 In an observational study among a high CV risk population of men, TRT with normalisation of TT levels was associated with decreased all-cause mortality.79 For more information about the wide range of health benefits of testosterone therapy, see "Health benefits of testosterone therapy in men with hypogonadism".

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    Diagnosis and controversies

    Correct diagnosis of hypogonadism is essential before treatment is initiated. However, how to make the diagnosis of hypogonadism has been the subject of controversy; there is debate about threshold testosterone levels for defining hypogonadism, the ideal procedure for measuring testosterone levels (time of day, fasting vs non-fasting, laboratory methods), and whether total testosterone, free testosterone, or bioavailable testosterone is the most appropriate testosterone fraction to use when evaluating androgen status and making the diagnosis of hypogonadism.

    However, hypogonadism and testosterone therapy are an active area of research, which is expected to close the current knowledge gaps. For more information about recommendations of recent clinical guidelines on hypogonadism, issued by different medical societies, see "Hypogonadism Treatment Guidelines".

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