3 Male Hypogonadism

Suggested citation:  Endocrine Society. Endocrine Facts and Figures: Reproduction and Development. First Edition. 2017

As men age past 30 years, circulating testosterone (T) declines progressively by 0.4 to 2% per year 40-42. Symptoms of androgen deficiency may include decreased energy, mood, muscle mass and strength, erectile function, bone density, and libido 43. Erectile dysfunction, low libido, and lack of morning erections are the symptoms that are most specific for male hypogonadism 44.

Table 3. Symptoms and signs of androgen deficiency in men.
A. More specific symptoms and signs
    Breast discomfort, gynecomastia
    Incomplete or delayed sexual development, eunuchoidism
    Reduced sexual desire (libido) and activity
    Inability to father children, low or zero sperm count
    Decreased spontaneous erections
    Hot flushes, sweats
    Loss of body (axillary and pubic) hair, reduced shaving
    Very small (especially <5 ml) or shrinking testes
    Height loss, low trauma fracture, low bone mineral density
B. Other less specific symptoms and signs
    Diminished physical or work performance
    Decreased energy, motivation, initiative, and self-confidence
    Poor concentration and memory
    Feeling sad or blue, depressed mood, dysthymia
    Increased body fat, BMI
    Sleep disturbance, increased sleepiness
    Mild anemia (normochromic, normocytic, in the female range)
    Reduced muscle bulk and strength
Abbreviations: BMI, body mass index.

Source: Bhasin et al. 2011 45


One US study on osteoporosis and androgens in a cohort of 2,447 men (mean age 73 years) reported that 3.0% had T deficiency (the study defined T deficiency as less than 200 ng/dl) 46.

A study on trends in T prescribing practices in the US, reported that from 2001 to 2011 T use more than tripled among men 40 years or older (0.81% in 2001 to 2.91% in 2011) 47 (Table 4). In 2011, 2.29% of men in their 40s and 3.75% of men in their 60s were taking androgen replacement therapy. The study looked at four formulations and concluded that men most commonly used topical gels. It also reported that gel use had the highest rate of increase—more than 5-fold 47.

In 2010 (geographically in the US) the South had the highest prevalence of T use (3.77% for men 40 years of age or older), the West had the second highest prevalence (2.61%), followed by the Midwest (1.78%), and the Northeast (1.60%) 47.

A European study that included 3,334 men aged 40-79 years reported that 80% had normal total T (TT) and normal free T (FT), 8% had normal TT and low FT, 3% had low TT and normal FT, and 9% had low TT and low FT 48. Normal TT and low FT were associated with advanced age and poorer health; whereas, low TT and normal FT were associated with younger age and obesity. Low FT, even in those with normal TT, was associated with classical symptoms of androgen deficiency (such as sexual dysfunction). Therefore, clinicians should assess FT levels in men suspected of having androgen deficiency.

Table 4. Percentage of men in the United States given androgen replacement therapy by age group and year.
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
N 624,080 670,126 703,738 698,074 724 518 715,546 720 046 761,088 729,965 698,380 698,343
% Given ART 0.54 0.66 0.76 0.75 0.81 0.90 1.05 1.22 1.66 1.99 2.29
Age 50-59
N 424,534 457,417 490,381 501,335 562,482 578,941 605,057 675,508 639,073 625,709 643,106
% Given ART 1.02 1.19 1.39 1.36 1.37 1.52 1.69 1.88 2.54 2.98 3.26
Age 60-69
N 161,273 182,399 197,578 204,055 234,902 250,808 280,662 331,150 309,766 300,312 317,143
% Given ART 1.32 1.53 1.72 1.68 1.69 1.87 2.06 2.28 3.03 3.51 3.75
Age ≥70
N 60,925 69,210 71,445 73,181 93,855 95,678 104,750 113,813 103,342 82,203 84,875
% Given ART 0.77 0.79 0.99 0.99 1.00 1.13 1.20 0.96 1.92 2.10 2.22
All ages
N 1,270,812 1,379,062 1,463,142 1,476,645 1,615,757 1,640,973 1,710,515 1,881,559 1,782,146 1,706,604 1,743,467
% Given ART 0.81 0.96 1.11 1.10 1.14 1.20 1.45 1.66 2.23 2.63 2.91
Abbreviations: ART, androgen replacement therapy; N, number of eligible men

Source: Baillargeon et al. 2013 47


T gels, patches, buccal tablets, nasal sprays and subcutaneous pellets are quite expensive. For example, the topical gel Androgel© 1% (50 mg to 100 mg/day), costs roughly US $5,000- $10,000/year 49,50. Intramuscular T esters (cypionate, enanthate) are much more affordable with a maximum recommended dose of 400 mg per month, which equates to an average cost of between US $100-200/year 51,52.

Handelsman et al. reported that T purchases increased at a compound global annual growth rate of 25% from 2000 to 2011 (from approximately US $165 million to $2 billion). During the same time period, sales in the US increased at a compound annual growth rate of 23% 53.


Male androgen deficiency increases as men age. The majority of studies have not shown significant difference in T levels or symptom of T-deficiency between races 54,55 (Table 5).

Table 5. Total and free testosterone and sex hormone binding globulin levels overall by race/ethnic group.
Variable Overall n=1,845 White n=681 Black n=523 Hispanic n=641
TT, ng/dl 437.8 ± 180.1 433.7 ± 171.7 447.3 ± 196.5 439.4 ± 186.8
FT, ng/dl 9.1 ± 3.7 9.0 ± 3.5 9.3 ± 4.0 9.4 ± 3.9
TT < 300 ng/dl 457 (24.3) 179 (24.0) 122 (26.6) 156 (21.2)
FT < 5 ng/dl 218 (10.6) 85 (10.2) 63 (12.4) 70 (8.8)
TT by FT category
    TT <300 ng/dl, FT <5 ng/dl 186 (9.3) 74 (9.2) 49 (10.2) 63 (7.9)
     TT >300 ng/dl, FT ≥5 ng/dl 271 (15.0) 105 (14.8) 73 (16.4) 93 (13.3)
     TT ≥300 ng/dl, FT >5 ng/dl 32 (1.3) 11 (1.0) 14 (2.2) 7 (0.9)
     TT ≥300 ng/dl, FT ≥5 ng/dl 1,356 (74.4) 491 (75.0) 387 (71.2) 478 (77.9)
SHBG, nmol/liter (move to lowest row as T values are the most important) 34.0 ± 17.7 34.0 ± 16.6 35.2 ± 20.7 31.9 ± 16.2
Abbreviations: T, testosterone; SHBG, sex hormone binding globulin; FT, free testosterone; TT, total testosterone.

Source: Araujo et al. 2007 55


Studies have associated low T levels with metabolic syndrome (MetS), decreased muscle strength, hyperinsulinemia, diabetes mellitus, bone loss and osteoporosis, loss of libido, erectile dysfunction, depression, lethargy, inability to concentrate, sleep disturbance, irritability, depression, regression of secondary sex characteristics, and decreased interest in activities 46,56-66. These signs and symptoms are associated with low T and not proven to be causative. Thus, low T may be a reflection of overall poor health.

A study by Sharma et al. 67 (Table 6) reported that normalizing T levels via T replacement therapy resulted in a significant reduction in all-cause mortality, myocardial infarction, and stroke.

In contrast, Araujo et al. 66 reported a week association between endogenous sex steroid levels and mortality. In addition, the European Male Aging Study found that having and/or developing CVD was not associated with T levels after adjusting for age, BMI, and comorbidities (Table 7) 48.

There was a great deal of interest when two publications using large pharmacoepidemiologic databases, suggested that T use was associated with an increased risk of having a cardiovascular event. There were many criticisms of these studies, including the fact that approximately one-third did not have documented T levels prior to therapy. However, it did lead to the US Food and Drug Administration changing its labeling to discourage the use of T in men with age-related declines in T. Recently, studies of men older than 65 years with low T levels found that T treatment was associated with improved bone density and hematocrit, without any change in cognition or carotid plaque volume. Larger studies are now being planned which are sufficiently powered for heart disease outcomes 68-71.

Table 6. Unadjusted and adjusted hazard ratios for all-cause mortality, myocardial infarction, and stroke associated with testosterone treatment for low testosterone in men.
Model  All-cause mortality Myocardial infarction  Stroke
  Hazard ratio  95% CI  P value Hazard ratio   95% CI  P value Hazard ratio  95% CI  P value
Comparing non-normalized treated versus untreated (reference = untreated)
Univariate N = 25,701 versus 13,378 0.83 0.79-0.87 <0.001 0.95 0.79-1.15 0.599 0.90 0.61-1.34 0.610
Propensity matched (stabilized inverse probability of treatment weights) N = 23,953 versus 11,957 0.84 0.80-0.89 <0.001 0.98 0.80-1.19 0.811 0.94 0.61-1.44 0.675
Comparing normalized treated versus untreated (reference = untreated) 
Univariate N = 43,931 versus 13,378 0.40 0.39-0.43 <0.001 0.70 0.59-0.83 <0.001 0.57 0.40-0.82 0.002
Propensity matched (stabilized inverse probability of treatment weights) N = 40,852 versus 11,957 0.44 0.42-0.46 <0.001 0.76 0.63-0.93 0.005 0.64 0.43-0.96 0.031
Comparing normalized treated versus non-normalized treated (reference = non-normalized treated) 
Univariate N = 43,931 versus 25,701 0.49 0.47-0.51 <0.001 0.74 0.64-0.85 <0.001 0.64 0.48-0.87 0.004
Propensity matched (stabilized inverse probability of treatment weights) N = 40,852 versus 23,953 0.53 0.50-0.55 <0.001 0.82 0.71-0.95 0.008 0.70 0.51-0.96 0.028
Abbreviations: N, number; CI, confidence interval.

Source: Sharma et al. 2015 67

Table 7. Association among testosterone status and cardiovascular disease, metabolic syndrome, and all-cause mortality.
Normal TT Low TT Low TT
Low cFT  Normal cFT  Low cFT 
OR (95% CI) OR (95% CI) OR (95% CI)
Having CVD    
Unadjusted 2.15 (1.67, 2.75)*** 1.57 (1.04, 2.36)* 2.44 (1.93, 3.08)***
Age, center, BMI, comorbidities 0.83 (0.60, 1.15) 1.69 (0.94, 3.03) 1.00 (0.73, 1.37)
Having MetS       
Unadjusted 1.94 (1.48, 2.55)*** 4.13 (2.70, 6.33)*** 4.02 (3.13, 5.17)***
Age, center, BMI, comorbidities 1.32 (0.94, 1.86) 2.55 (1.54, 4.22)*** 1.60 (1.17, 2.18)**
Developing CVD       
Unadjusted 1.72 (1.09, 2.72)* 1.56 (0.83, 2.95) 1.80 (1.18, 2.74)**
Age, center, BMI, comorbidities 1.06 (0.64, 1.73) 1.41 (0.72, 2.76) 1.17 (0.74, 1.85)
Developing MetS       
Unadjusted 1.59 (0.94, 2.70) 2.53 (1.11, 5.76)* 2.39 (1.43, 4.00)**
Age, center, BMI, comorbidities 1.34 (0.74, 2.42) 1.45 (0.59, 3.53) 1.65 (0.93, 2.93)
All-cause mortality       
Unadjusted 2.62 (1.93, 3.56)*** 1.15 (0.75, 1.75) 2.70 (2.02, 3.60)***
Age, center, BMI, comorbidities 1.24 (0.89, 1.73) 1.21 (0.77, 1.91) 1.63 (1.18, 2.24)**
Abbreviations: CI, confidence interval; CVD, cardiovascular disease; OR, odds ratio; BMI, body mass index; MetS, metabolic syndrome; TT total testosterone, cFT, calculated free testosterone.
Notes: Data are reported as hazard ratios (95% CI), with normal TT/normal cFT as the referent group; *,  p < .05; ** , p < .01; ***P < .001

Source: Antonia et al. 2016 48


3.5.1. Appropriate Levels

Experts don’t agree on what androgen levels are “normal” for healthy, aging men. Mohr et al. proposed age-specific thresholds of 251, 216, 196, and 156 ng/dl for men in their 40s, 50s, 60s, and 70s (respectively). These thresholds correspond to the bottom 2.5th percentile of the data in the study 72.

A European study of T and hypogonadism in 3,369 men aged 40 to 79 years defined late-onset hypogonadism as the presence of at least three sexual symptoms associated with a TT level of <3.2 ng per milliliter and a FT level of <64 pg per milliliter: poor morning erection, low sexual desire, and erectile dysfunction 44.

Clinicians should diagnose androgen deficiency only if a patient has unequivocally low serum T levels and consistent symptoms and signs. Initial diagnostic tests should use a reliable assay to measure morning TT levels, and levels should be confirmed by repeating this measurement, along with serum gonadotropin levels to identify an etiology. Clinicians should measure free or bioavailable T levels in some men with TT near the lower limit of normal or in men with suspected sex hormone-binding globulin abnormalities due to age or obesity 45.

Table 8. Conditions where clinicians should consider measure serum testosterone levels.
Osteoporosis or low trauma fracture, especially in a young man
Sellar mass, radiation to the sellar region, or other diseases of the sellar region
End-stage renal disease and maintenance hemodialysis
Treatment with medications that affect T production or metabolism, such as glucocorticoids and opioids
HIV-associated weight loss
Moderate to severe chronic obstructive lung disease
Abbreviations: T2DM, type 2 diabetes mellitus.

Source: Bhasin et al. 2010 45

3.5.2. Treatment

T therapy is recommended for symptomatic androgen deficiency in men to develop and maintain secondary sex characteristic and improve sense of well-being, muscle mass and strength, bone mineral density, and sexual function 45. Clinicians treating patients with any of the approved formulations should try to maintain T levels in the mid-normal range 45.

One study reported that treatment with transdermal 2% T gel over a 6-month had beneficial effects on insulin resistance, total and LDL-cholesterol, lipoprotein(a), and sexual health in hypogonadal men with type 2 diabetes (T2DM) and/or MetS 73.

Another study examined combined treatments of various strengths of T gel with medications to suppress endogenous T and/or suppress the conversion of T to estradiol in 198 healthy 20- to 50-year-old men 74. The study reported that a wide variety of levels of T were needed to maintain lean mass, fat mass, strength, and sexual function and recommended that clinicians should reassess both the evaluation and management of hypogonadism in men 74.

A third study examined 790 men 65 years of age or older who had low T levels and symptoms that suggested hypoandrogenism. The study reported that increasing T concentrations from moderately low to the mid-normal range (corresponding to concentrations in men age 19-40 years) for 1 year had a moderate benefit regarding sexual function, some benefit regarding mood and depressive symptoms, but no benefit regarding vitality or walking distance 75.

Although the data is not consistent, the package insert for T still indicates that clinicians should not start T therapy in patients with breast or prostate cancer; hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, or uncontrolled or poorly controlled heart failure 45.

In summary, T therapy is clearly indicated in younger men with clear etiologies for their hypogonadism. The long-term benefits and risks of increasing T levels in older men are unclear 75.

Table 9. General clinical guidelines on testosterone treatments for male androgen deficiency. 
Formulation Pharmacokinetic profile Regimen DHT and E2 Advantages Disadvantages
Transdermal T patch Treatment restores serum T, DHT, and E2 levels to the physiological male range. 1 or 2 patches, designed to nominally deliver 5-10 mg T over 24 h applied every d on nonpressure areas T:DHT and T:E2 levels are in the physiological male range. There is relative ease of application, and treatment corrects symptoms of androgen deficiency. Serum T levels in some androgen-deficient men may be in the low-normal range; these men may need to apply two patches daily; skin irritation at the application site occurs frequently in many patients.
T enanthate or cypionate Depending on the dose, after a single IM injection, serum T levels rise into the supraphysiological range, then decline gradually into the hypogonadal range by the end of the dosing interval. 150-200 mg IM every 2 wk or 75-100 mg/wk DHT and E2 levels rise in proportion to the increase in T levels; T:DHT and T:E2 ratios do not change. Treatment corrects symptoms of androgen deficiency; it is relatively inexpensive when self-administered; there is dosing flexibility. Treatment requires IM injection; serum T levels have peaks and valleys; treatment has been associated with erythrocytosis.
T pellets Serum T peaks at 1 month and then is sustained in normal range for 3-6 months, depending on formulation. 3-10 pellets implanted SC; dose and regimen vary with formulation T:DHT and T:E2 ratios do not change. Treatment corrects symptoms of androgen deficiency. Treatment requires surgical incision for insertions; pellets may extrude spontaneously.
1%, 1.62%, or 2% T gel Restores serum T and E2 levels to the physiological male range. Available in sachets, tubes and pumps 5-10 g T gel containing 50-100 mg T every d. Serum DHT levels are higher and T:DHT ratios are lower in hypogonadal men treated with the T gel than in healthy eugonadal men. Treatment corrects symptoms of androgen deficiency; there is dose flexibility, ease of application, and good skin tolerability. There is the potential of transfer to a female partner or child by direct skin-to-skin contact; a small proportion of treated men reported skin irritation; there are moderately high DHT levels.
Buccal, bioadhesive, T tablets It is absorbed from the buccal mucosa. 30 mg controlled release, bioadhesive tablets twice daily Treatment normalizes serum T and DHT levels in hypogonadal men. Treatment corrects symptoms of androgen deficiency in healthy, hypogonadal men. There are gum-related adverse events in 16% of treated men.
T-in-adhesive matrix patch It restores serum T, DHT and E2 to the physiological range. 2 × 60 cm2 patches delivering approximately 4.8 mg T/d T:DHT and T:E2 are in the physiological range. Treatment lasts 2 d. There is some skin irritation.
Oral T undecanoate When administered in oleic acid, T undecanoate is absorbed through the lymphatics, bypassing the portal system; there is considerable variability in the same individual on different days and among individuals. 40-80 mg orally, twice daily or three times daily with meals There is a high DHT:T ratio. There is the convenience of oral administration. It is not approved in the US; there are variable clinical responses, variable serum T levels, and a high DHT:T ratio.
Injectable long-acting T undecanoate in oil When administered at a dose of 750 to 1,000 mg IM, serum T levels are maintained in the normal range in a majority of treated men. European regimen 1,000 mg IM, followed by 1,000 mg at 6 wk, and 1,000 mg every 10-14 wk DHT and E2 levels rise in proportion to the increase in T levels; T:DHT and T:E2 ratios do not change. Treatment corrects symptoms of androgen deficiency; requires infrequent administration. Treatment requires IM injection of a large volume (4 ml); a very small number of men reported coughing immediately after injection.
Abbreviations: T, testosterone; IM, intramuscular; d, day; wk, week; SC, subcutaneous; DHT, dihydrotestosterone; E2, estradiol; US, United States.

Source: Bhasin et al. 201145

Table 10. Individual studies on various testosterone therapies for male androgen deficiency.
Medications Subjects Regimen Results Reference
Novel transdermal 2% T 220 hypogonadal men with T2DM and/or MetS I 12-month treatment Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health. H Jones et al. 2011 73
T gel 790 men 65 years of age or older with a serum T concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism Treated for 1 year Raising T concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. Snyder et al. 2016 75


T gel (with goserelin acetate and anastrozole to suppress T and E2) Group A: 198 healthy men 20 to 50 years of age

Group B: 202 healthy men 20 to 50 years of age

Group A. Treatment with goserelin acetate (to suppress endogenous T and E2) and randomly assigned to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of T gel daily for 12 weeks

Group B: Treatment with goserelin acetate, placebo gel or T gel, and anastrozole (to suppress the conversion of T to E2).

The percentage of body fat increased in subjects receiving placebo or 1.25 g or 2.5 g of T daily without anastrozole (mean T level, 44±13 ng per deciliter, 191±78 ng per deciliter, and 337±173 ng per deciliter, respectively).

Lean mass and thigh-muscle area decreased in subjects receiving placebo and in those receiving 1.25 g of T daily without anastrozole.

Leg-press strength fell only with placebo administration. In general, sexual desire declined as the T dose was reduced.

Finkelstein et al. 2013 74
Abbreviations: T, testosterone; T2DM, type 2 diabetes mellitus; MetS, metabolic syndrome; E2, estradiol.


Table 11. Potential adverse effects of testosterone replacement.
Adverse events for which there is evidence of association with T administration
Growth of metastatic prostate cancer
Reduced sperm production and fertility
Acne and oily skin
Detection of subclinical prostate cancer
Uncommon adverse events for which there is weak evidence of association with T administration
Male pattern balding (familial)
Growth of breast cancer
Induction or worsening of obstructive sleep apnea
Formulation-specific adverse effects
Intramuscular injections of T enanthate, or cypionate
Pain at injection site
Fluctuation in mood or libido
Excessive erythrocytosis (especially in older patients)
Intramuscular injections of T undecanoate a
Coughing episodes immediately after the IM injection
Injection site pain
Transdermal patches
Frequent skin reactions at application site
Transdermal gel
Potential risk for T transfer to partner or another person who is in close contact (need to remind patient to cover application sites with clothing and to wash skin and hands with soap before having skin-to- skin contact with another person)
Skin irritation
Buccal T tablets
Irritation of gums
Alterations in taste
Pellet implants
Infection, expulsion of pellet
Oral tablets b
Effects on liver and cholesterol (methyltestosterone)
Abbreviations: T, testosterone.
Notes: a, data on undecanoate from Zitzman et al. 201376; b, liver toxicity has been reported mostly with oral 17-alkylated androgens. 

Source: Bhasin et al. 2010 45

Table 12. Conditions where testosterone administration is a concern for an association with a high risk of adverse outcome and not recommended.
Very high risk of serious adverse outcomes
    Metastatic prostate cancer*
    Breast cancer
Moderate to high risk of adverse outcomes
    Unevaluated prostate nodule or induration*
    PSA >4 ng/ml (>3 ng/ml in individuals at high risk for prostate cancer, such as African- Americans or men with first-degree relatives who have prostate cancer)*
    Hematocrit >50%
    Severe lower urinary tract symptoms associated with benign prostatic hypertrophy as indicated by AUA/IPSS >19*
    Uncontrolled or poorly controlled congestive heart failure
Note: *, data are poor.

Source: Bhasin et al. 2010 45


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