About hypogonadism

    What is hypogonadism (also known as testosterone deficiency or low testosterone)?

    Hypogonadism is a well-established medical condition that negatively affects male sexuality, reproduction, quality of life, general health and longevity.1,2 Hypogonadism is characterized by low testosterone levels or insufficient testosterone action, with accompanying symptoms and signs,1,2 particularly low sexual desire, erectile dysfunction, poor morning erections, inability to perform vigorous activity, depressed mood and fatigue.3

    Hypogonadism results from reduced testicular synthesis of testosterone due to:1

    • Impaired Leydig cell function (primary hypogonadism, also known as hypergonadotropic hypogonadism) – seen in patients with Klinefelter’s and testicular cancer, and also common in older men.
    • Inadequate LH gonadotropic stimulation of Leydig cells (secondary hypogonadism, also known as hypogonadotropic hypogonadism) – most common in men with overweight/obesity and type 2 diabetes.

     

    Hypogonadism may result from either of these causes or from a combination of causes (mixed hypogonadism).

    Hypogonadism symptoms can appear in the presence of total testosterone levels within the normal reference range, due to:4

    • Elevated sex hormone-binding globulin (SHBG), resulting in a reduction in free testosterone levels.
    • Low androgen receptor sensitivity (which is genetically determined).
    • Androgen receptor blockade (by medications)

     

    Hypogonadism can occur in men of any age; therefore the terms ’late-onset hypogonadism’ and ’age-related hypogonadism’ are misleading and should be discarded.5-7 The term ‘andropause’ has been used as a synonym for hypogonadism, with claims that it is the “male version of menopause”. While some symptoms of andropause are similar to menopause, drawing this parallel is erroneous because not all men develop hypogonadism, and in those who do, testosterone levels have declined progressively over an extended period of time.8 In contrast, menopause affects all women universally and occurs quite abruptly.

    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 Aging Male (ISSAM).2 The impetus for this meeting was to address the widespread misinformation and confusion about hypogonadism and testosterone therapy.9 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 summarized in table 1.2

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

    ResolutionsExpert 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 healthy volunteers or patients who undergo androgen deprivation; these symptoms and signs resolve with T normalization.
    • Historically recognized 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 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,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.

    • 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).
    • The largest meta-analysis showed no increased risk with T therapy; reduced risk was noted in men with metabolic conditions.
    • No increased risk of blood clots (VTE) with T therapy.

    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.

    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 reliably increases lean mass, decreases fat mass, and may improve glycemic control.
    • 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 normalized T levels had a reduced rate of CV events/ mortality vs men with persistently low T.

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

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

    Among men aged >45 years visiting primary care offices, the prevalence of hypogonadism has been shown to be nearly 40%.10 In men with obesity (BMI ≥30 kg/m²), hypogonadism was present in up to 58%, despite the relatively young age of 43 years,11 while in a population of men with severe obesity (age 40 years) referred for bariatric surgery, nearly 80% had hypogonadism.12

    Men with type 2 diabetes tend to have a higher prevalence of low free testosterone than low total testosterone.13-15 For instance, in one study 43% of men with type 2 diabetes had low total testosterone, and 57% had low free testosterone (calculated).13 In another study of men with type 2 diabetes, 49% had low total testosterone while 58% had low free testosterone.14 Yet another study found that 45% and 61% of men with type 2 diabetes had low total and calculated free testosterone levels, respectively.15 Based on either total or free testosterone being low, prevalence was 69%.14 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%.6

    Among men with erectile dysfunction, up to half (47%) 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.16

    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.17 In 2014, the global age-standardised prevalence of type 2 diabetes in men had increased from 4.3% in 1980 to 9.0%.18  Rising levels of adiposity explain the large majority of the rise in diabetes prevalence,19 and obesity is considered the main preventable and treatable cause of type 2 diabetes.20 The prevalence of prediabetes is alarmingly high at 58%.21 In the Massachusetts Male Aging Study (MMAS), the prevalence of erectile dysfunction was 52% in 40- to 70-year-old men in the general population.22 Obesity is also a strong risk factor for erectile dysfunction.23

    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.24 Likewise, all men with type 2 diabetes should be evaluated to exclude testosterone deficiency.24 In 2018, the American Diabetes Association (ADA) added to their Standards of Medical Care in Diabetes the recommendation to measure serum testosterone in men with diabetes and signs and symptoms of hypogonadism,25 and expert clinicians have also made a strong case for measuring total testosterone and calculating free testosterone in routine diabetic care.14

    While the prevalence of hypogonadism commonly increases with age, this is not due to aging per se, but rather due to accumulation of comorbidities with aging. Weight gain / obesity is strongly linked to incident low testosterone levels and development of hypogonadism,26-28 as is enlarged waist circumference, dyslipidemia, metabolic syndrome and type 2 diabetes.29 Notably, the additional decline in testosterone levels associated with moving from a non-obese to an obese state in the MMAS (or an increase in BMI of 4 kg/m2 ) is comparable to that associated with 10 years of aging among men who remain at a healthy weight.27

    Testosterone is not just a sexual hormone, it is also a metabolic hormone and vascular hormone that plays a critical role in metabolic and vascular health.30,31 The metabolic effects of testosterone explain why low testosterone contributes to the development of obesity, metabolic syndrome and type 2 diabetes.31-36 Testosterone is also a vasoactive hormone with predominantly vasodilatory actions.30 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.30,37 Testosterone affects vascular tone by acting as an L-calcium channel blocker and by inducing potassium channel activation in vascular smooth muscle cells.30 Testosterone is beneficially associated with key mediators of atherosclerosis,38 including lipids,39,40 endothelial dysfunction41 and inflammation.42 Higher testosterone levels are also associated with less atherosclerotic burden, as measured by carotid intima-media thickness.43-45 Hence, low testosterone is a marker of cardiovascular risk, and may even be a cardiovascular risk factor itself.46,47

    Emerging research suggests that testosterone, or its metabolite DHT, may be positively associated with telomere length, which is a cellular marker for biological aging.48,49 Experimental studies have shown that testosterone prevents vascular smooth muscle cell senescence and delays vascular and cardiomyocyte aging.50,51

    In addition to physical and metabolic effects, testosterone plays a key role for mood, mental health and cognitive function.52,53 Men with low testosterone levels have a 4-fold increased risk of developing depression over the next two years.54 In these men, the prevalence of anxiety disorders, depressed mood and major depressive disorder is significantly higher than in men with healthy levels of testosterone.54-56 Vice versa, men with depression have significantly lower total and free testosterone concentrations than nondepressed men.57 It has been suggested that low testosterone may be a potentially treatable cause of depressive symptoms.57 The link between low testosterone and depressive symptoms is seen in both young men (below 40 years old) 58 and older men.59 It has been suggested that testosterone may have protective effects against anxiety and depression, and explain why women are more than twice as likely to be afflicted by anxiety and depression.52 High testosterone levels predicted better performance on several tests of cognitive function.60

    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.47

    It is very important to treat men with hypogonadism because hypogonadism is associated with increased cardiovascular and all-cause mortality,61-64 independent of waist circumference, smoking habits, high-risk alcohol use, physical activity and renal insufficiency.65 Notably, the association between low testosterone and all-cause mortality persists even after adjustment for age and co-morbidities.62,65,66 It is noteworthy that even young men with low testosterone are at increased risk of death.65

    Critically, a growing body of evidence shows that testosterone therapy in men with hypogonadism reduces mortality compared to men with hypogonadism who do not receive testosterone therapy.67-76 Importantly, testosterone therapy reduces premature mortality even in men with existing heart disease.77,78 For more information about the wide range of health benefits of testosterone therapy, see "Health benefits of testosterone therapy in men with hypogonadism".

    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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